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Bellini G, D'Antongiovanni V, Palermo G, Antonioli L, Fornai M, Ceravolo R, Bernardini N, Derkinderen P, Pellegrini C. α-Synuclein in Parkinson's Disease: From Bench to Bedside. Med Res Rev 2025; 45:909-946. [PMID: 39704040 PMCID: PMC11976381 DOI: 10.1002/med.22091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 09/24/2024] [Accepted: 11/07/2024] [Indexed: 12/21/2024]
Abstract
α-Synuclein (α-syn), a pathological hallmark of PD, is emerging as a bridging element at the crossroads between neuro/immune-inflammatory responses and neurodegeneration in PD. Several evidence show that pathological α-syn accumulates in neuronal and non-neuronal cells (i.e., neurons, microglia, macrophages, skin cells, and intestinal cells) in central and peripheral tissues since the prodromal phase of the disease, contributing to brain pathology. Indeed, pathological α-syn deposition can promote neurogenic/immune-inflammatory responses that contribute to systemic and central neuroinflammation associated with PD. After providing an overview of the structure and functions of physiological α-syn as well as its pathological forms, we review current studies about the role of neuronal and non-neuronal α-syn at the crossroads between neuroinflammation and neurodegeneration in PD. In addition, we provide an overview of the correlation between the accumulation of α-syn in central and peripheral tissues and PD, related symptoms, and neuroinflammation. Special attention was paid to discussing whether targeting α-syn can represent a suitable therapeutical approach for PD.
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Affiliation(s)
- Gabriele Bellini
- Center for Neurodegenerative Diseases, Unit of Neurology, Parkinson's Disease and Movement Disorders, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
- Department of NeurologyThe Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU Langone HealthNew York CityNew YorkUSA
| | - Vanessa D'Antongiovanni
- Unit of Histology and Embryology, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Giovanni Palermo
- Center for Neurodegenerative Diseases, Unit of Neurology, Parkinson's Disease and Movement Disorders, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Roberto Ceravolo
- Center for Neurodegenerative Diseases, Unit of Neurology, Parkinson's Disease and Movement Disorders, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Nunzia Bernardini
- Unit of Histology and Embryology, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Pascal Derkinderen
- Department of NeurologyNantes Université, CHU Nantes, INSERMNantesFrance
| | - Carolina Pellegrini
- Unit of Histology and Embryology, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
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2
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Cheng YK, Chiang HS. The interrelationship between intestinal immune cells and enteric α-synuclein in the progression of Parkinson's disease. Neurol Sci 2025:10.1007/s10072-025-08114-w. [PMID: 40085320 DOI: 10.1007/s10072-025-08114-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 03/07/2025] [Indexed: 03/16/2025]
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor impairment, resulting from the accumulation of α-synuclein and neuronal cell death in the substantia nigra of the midbrain. Emerging evidence suggests that α-synuclein aggregation may originate in the enteric nervous system (ENS) and subsequently propagate to the brain via the vagus nerve. Clinical observations, such as prodromal gastrointestinal dysfunction in PD patients and the increased incidence of PD among individuals with inflammatory bowel disease, support the hypothesis that abnormal intestinal inflammation may contribute to the onset of motor dysfunction and neuropathology in PD. This review examines recent findings on the interplay between intestinal immune cells and α-synuclein aggregation within the framework of gut-originated PD pathogenesis. It begins by discussing evidence linking dysbiosis and intestinal inflammation to α-synuclein aggregation in the ENS. Additionally, it explores the potential role of intestinal immune cells in influencing enteric neurons and α-synuclein aggregation, furthering the understanding of PD development.
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Affiliation(s)
- Yuan-Kai Cheng
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Hao-Sen Chiang
- Department of Life Science, National Taiwan University, Taipei, Taiwan.
- Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan.
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Han MN, Di Natale MR, Lei E, Furness JB, Finkelstein DI, Hao MM, Diwakarla S, McQuade RM. Assessment of gastrointestinal function and enteric nervous system changes over time in the A53T mouse model of Parkinson's disease. Acta Neuropathol Commun 2025; 13:58. [PMID: 40075409 PMCID: PMC11899089 DOI: 10.1186/s40478-025-01956-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/13/2025] [Indexed: 03/14/2025] Open
Abstract
Gastrointestinal (GI) dysfunctions, including constipation and delayed stomach emptying, are prevalent and debilitating non-motor symptoms of Parkinson's disease (PD). These symptoms have been associated with damage in the enteric nervous system (ENS) and the accumulation of pathogenic alpha-synuclein (α-Syn) within the GI tract. While motor deficits and dopaminergic neuron loss in the central nervous system (CNS) of the A53T mouse model are well-characterised, the temporal relationship between GI dysfunction, ENS pathology, and motor symptoms remains unclear. This study aimed to investigate functional alterations in the GI tract at the early stages of the disease, before the appearance of motor deficits, both in vivo and ex vivo. Early colonic motility deficits observed in A53T mice, measured via bead expulsion, preceded motor impairments emerged at 36 weeks. Although whole-gut transit remained unchanged, reduced faecal output was concurrent with marked colonic dysmotility at 36 weeks. Despite a lack of significant neuronal loss, a greater number of enteric neurons in A53T mice showed signs of neuronal hypertrophy and increased nuclear translocation of HuC/D proteins indicative of neuronal stress at 12 and 36 weeks. Calcium imaging revealed differential enteric neuron activity, characterised by exaggerated calcium transients at 12 weeks that normalized by 36 weeks. Furthermore, a reduction in enteric glial populations was observed as early as 12 weeks in both the ileum and colon of A53T mice. These findings provide compelling evidence that ENS pathology, including neuronal stress, disrupted calcium signalling, and glial cell loss, precedes the onset of motor symptoms and may contribute to early GI dysfunction in PD.
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Affiliation(s)
- Myat Noe Han
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia
| | - Madeleine R Di Natale
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Enie Lei
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia
| | - John B Furness
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia
| | - David I Finkelstein
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Marlene M Hao
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia
| | - Shanti Diwakarla
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia
| | - Rachel M McQuade
- Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia.
- Gut Barrier and Disease Laboratory, Department of Anatomy and Physiology, University of Melbourne, Parkville VIC, Melbourne, 3010, Australia.
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Isonaka R, Sullivan P, Goldstein DS. Pathophysiological Significance of α-Synuclein in Sympathetic Nerves: In Vivo Observations. Neurology 2025; 104:e210215. [PMID: 39805051 PMCID: PMC11735147 DOI: 10.1212/wnl.0000000000210215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 10/22/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND AND OBJECTIVES Lewy body diseases (LBDs) such as Parkinson disease (PD) feature increased deposition of α-synuclein (α-syn) in cutaneous sympathetic noradrenergic nerves. The pathophysiologic significance of sympathetic intraneuronal α-syn is unclear. We reviewed data about immunoreactive α-syn, tyrosine hydroxylase (TH, a marker of catecholaminergic fibers), and the sympathetic neurotransmitter norepinephrine (NE) in skin biopsies from control participants and patients with PD, the related LBD pure autonomic failure (PAF), the non-LBD synucleinopathy multiple system atrophy (MSA), or neurologic postacute sequelae of severe acute respiratory syndrome coronavirus 2 (neuro-PASC). METHODS In a retrospective observational study, we reviewed data about α-syn-TH colocalization indexes and immunoreactive α-syn and TH signal intensities in arrector pili muscles, blood vessels, and sweat glands from neck skin biopsies and NE concentrations in simultaneously obtained thigh skin biopsies from participants studied at the NIH Clinical Center. LBD, MSA, and control group data were assessed by analyses of variance with the Tukey post hoc test for multiple comparisons. Similar analyses were performed for patients with PD or neuro-PASC vs control. RESULTS Dermal α-syn-TH colocalization indexes and α-syn signal intensities from neck skin biopsies were examined in 18 controls (mean age 58 years, 50% female) and 53 LBD (66, 34%), 15 MSA (61, 33%), and 11 neuro-PASC (52, 82%) patients. The LBD group had higher α-syn-TH colocalization indexes than the controls (mean difference = 1.495, 95% CI 1.081-1.909, p < 0.0001) and increased α-syn signal intensities in all 3 skin constituents (arrector pili: mean difference = 2.743, 95% CI 1.608-3.879, p < 0.0001; blood vessels: mean difference = 2.157, 95% CI 1.095-3.219, p < 0.0001; sweat glands: mean difference = 4.136, 95% CI 1.704-6.567, p < 0.0001). The groups did not differ in either immunoreactive TH or NE. The neuro-PASC and PD groups had elevated α-syn-TH colocalization indexes compared with the controls, also with no group differences in immunoreactive TH or NE contents. DISCUSSION LBDs and neuro-PASC entail increased α-syn-TH colocalization indexes in skin biopsies, without evidence of local denervation or noradrenergic deficiency. The results fail to support toxicity of intraneuronal α-syn in cutaneous sympathetic noradrenergic nerves in either LBDs or neuro-PASC. The neuro-PASC data raise the possibility of sympathetic intraneuronal α-syn deposition as part of postinfectious immune or inflammatory processes.
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Affiliation(s)
- Risa Isonaka
- From the Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD
| | - Patti Sullivan
- From the Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD
| | - David S Goldstein
- From the Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD
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Casini A, Vivacqua G, Ceci L, Leone S, Vaccaro R, Tagliafierro M, Bassi FM, Vitale S, Bocci E, Pannarale L, Carotti S, Franchitto A, Mancini P, Sferra R, Vetuschi A, Latella G, Onori P, Gaudio E, Mancinelli R. TNBS colitis induces architectural changes and alpha-synuclein overexpression in mouse distal colon: A morphological study. Cell Tissue Res 2025; 399:247-265. [PMID: 39656240 PMCID: PMC11787265 DOI: 10.1007/s00441-024-03932-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 11/11/2024] [Indexed: 02/02/2025]
Abstract
Alpha-synuclein (α-syn) is widely expressed in presynaptic neuron terminals, and its structural alterations play an important role in the pathogenesis of Parkinson's disease (PD). Aggregated α-syn has been found in brain, in the peripheral nerves of the enteric nervous system (ENS) and in the intestinal neuroendocrine cells during synucleinopathies and inflammatory bowel disorders. In the present study, we evaluated the histomorphological features of murine colon with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, a common model of colitis. Thereafter, we investigated the expression of α-syn, Toll-like receptor 4 (TLR4), choline acetyltransferase (ChAT), vasoactive intestinal peptide (VIP), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), and calcitonin-like receptor (CALCR). Finally, we investigated the presence of phosphorylated α-syn (pS129 α-syn) aggregates and their relationship with inflammatory cells. Colon from TNBS mice showed an increase in inflammatory cells infiltrate and significative changes in the architecture of the intestinal mucosa. α-Syn expression was significantly higher in inflamed colon. VIP was increased in both the mucosa and muscularis externa of TNBS mice, while TH, CGRP, and CALCR were significantly reduced in TNBS mice. Amyloid aggregates of pS129 α-syn were detectable in the ENS, as in the macrophages around the glands of the mucosa correlating with the markers of inflammation. This study describes - for the first time - the altered expression of α-syn and the occurrence of amyloid α-syn aggregates in the inflammatory cells under colitis, supporting the critical role of bowel inflammation in synucleinopathies and the involvement of α-syn in IBD.
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Affiliation(s)
- Arianna Casini
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Giorgio Vivacqua
- Integrated Research Center (PRAAB), Campus Biomedico University of Rome, Rome, Italy
| | - Ludovica Ceci
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Stefano Leone
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Rosa Vaccaro
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Marco Tagliafierro
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Filippo Maria Bassi
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Sara Vitale
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Emanuele Bocci
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Luigi Pannarale
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Simone Carotti
- Integrated Research Center (PRAAB), Campus Biomedico University of Rome, Rome, Italy
| | - Antonio Franchitto
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy
| | - Patrizia Mancini
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Roberta Sferra
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Antonella Vetuschi
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Giovanni Latella
- Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health & Environmental Sciences, San Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza University of Rome, Via Alfonso Borelli 50 - 00161, Rome, Italy.
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Gao V, Crawford CV, Burré J. The Gut-Brain Axis in Parkinson's Disease. Cold Spring Harb Perspect Med 2025; 15:a041618. [PMID: 38772708 PMCID: PMC11694753 DOI: 10.1101/cshperspect.a041618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2024]
Abstract
Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut-brain axis for the development of biomarkers and disease-modifying treatments.
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Affiliation(s)
- Virginia Gao
- Appel Institute for Alzheimer's Disease Research and Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021, USA
- Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medicine, New York, New York 10065, USA
- Division of Movement Disorders, The Neurological Institute of New York, Columbia University Irving Medical Center, New York, New York 10033, USA
| | - Carl V Crawford
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York 10065, USA
| | - Jacqueline Burré
- Appel Institute for Alzheimer's Disease Research and Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021, USA
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Pasquini J, Brooks DJ, Pavese N. The involvement of the cholinergic system in Parkinson disease. HANDBOOK OF CLINICAL NEUROLOGY 2025; 211:215-229. [PMID: 40340062 DOI: 10.1016/b978-0-443-19088-9.00001-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
In Parkinson disease (PD), cholinergic dysfunction develops in the early stages of the neurodegenerative process and progresses over time. Basal forebrain cholinergic system dysfunction is historically linked to cognitive decline in the dementia spectrum, and its pathophysiologic role in PD-related cognitive impairment has now been well established. However, cholinergic system dysfunction is also linked to several other manifestations of PD, such as gait difficulties, REM sleep behavior disorder (RBD), neuropsychiatric manifestations such as depression and visual hallucinations, and olfactory dysfunction. Furthermore, disruption of the striatal intrinsic cholinergic system, which modulates dopamine release, has been linked to cardinal motor manifestations and dyskinesia. Manifestations of cognitive decline, gait problems, falls, and RBD tend to cluster in a subset of people with PD, so that a "cholinergic phenotype" has been proposed. In this chapter, the involvement of the cholinergic system and its clinical correlates in PD will be discussed.
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Affiliation(s)
- Jacopo Pasquini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Clinical Ageing Research Unit, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - David J Brooks
- Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark
| | - Nicola Pavese
- Clinical Ageing Research Unit, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark.
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8
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Shin C, Kim SI, Park SH, Kim JM, Lee JY, Chung SJ, Kim JW, Ahn TB, Park KW, Shin JH, Lee CY, Lee HJ, Kong SH, Suh YS, Kim HJ, Yang HK, Jeon B. Diagnostic accuracy and predictors of alpha-synuclein accumulation in the gastrointestinal tract of Parkinson's disease. NPJ Parkinsons Dis 2024; 10:155. [PMID: 39147801 PMCID: PMC11327357 DOI: 10.1038/s41531-024-00766-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 07/29/2024] [Indexed: 08/17/2024] Open
Abstract
The only characteristic of alpha-synuclein (AS) accumulation in the gastrointestinal (GI) tract of Parkinson's disease (PD) found in pathological studies is the "rostrocaudal gradient," which describes the more frequent presence of AS accumulation in the upper GI tract than in the lower GI tract. This study aimed to determine the diagnostic accuracy and identify predictors of AS accumulation in the GI tract of PD patients. The frequency of AS accumulation in the GI tract was compared between PD patients (N = 97) who underwent radical GI surgery for cancer and individually matched controls (N = 94). We evaluated AS accumulation in the neural structures using phosphorylated AS immunohistochemistry. A multivariable logistic regression analysis was conducted to determine the predictors of AS accumulation in the GI tract of PD patients. The frequency of AS accumulation was significantly higher in PD patients (75.3%) than in controls (8.5%, p-value < 0.001). The sensitivity and specificity of the full-layer evaluation were 75.3% and 91.5%, respectively. When the evaluation was confined to the mucosal/submucosal layer, the sensitivity and specificity were 46.9% and 94.7%, respectively. The rostrocaudal gradient of AS accumulation was found in PD patients. The duration from symptom onset to surgery was significantly longer in PD patients with AS accumulation (4.9 ± 4.9 years) than in PD patients without AS accumulation (1.8 ± 4.1 years, p-value = 0.005). Both disease duration and rostrocaudal gradient independently predicted the presence of AS accumulation in the GI tract of PD patients. Our study suggests PD-related AS accumulation in the GI tract follows a temporally increasing but spatially static progression pattern.
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Affiliation(s)
- Chaewon Shin
- Department of Neurology, Chungnam National University Sejong Hospital, Chungnam National University College of Medicine, 20, Bodeum 7-ro, Sejong-si, Republic of Korea
| | - Seong-Ik Kim
- Department of Pathology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Sung-Hye Park
- Department of Pathology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Jong-Min Kim
- Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 173 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Jee-Young Lee
- Department of Neurology, SMG-SNU Boramae Medical Center, Seoul National University College of Medicine, 20 Boramae-ro 5-gil, Dongjak-gu, 07061, Seoul, Republic of Korea
| | - Sun Ju Chung
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
| | - Jae Woo Kim
- Department of Neurology, Dong-A University Hospital, 26 Daesingongwon-ro, Seo-gu, Busan, Republic of Korea
| | - Tae-Beom Ahn
- Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul, Republic of Korea
| | - Kye Won Park
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
- Pacific Parkinson Research Centre, University of British Columbia, Vancouver, BC, Canada
| | - Jung Hwan Shin
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Chan Young Lee
- Department of Neurology, Ewha Womans University Mokdong Hospital, 1071 Annyangcheon-ro, Yangcheon-gu, Seoul, Republic of Korea
| | - Hyuk-Joon Lee
- Department of Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Seong-Ho Kong
- Department of Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Yun-Suhk Suh
- Department of Surgery, Seoul National University Bundang Hospital, 82 Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Han-Joon Kim
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Han-Kwang Yang
- Department of Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
| | - Beomseok Jeon
- Department of Neurology, Chung-ang University Health Care System Hyundae Hospital, Namyangju-si, Gyeonggi-do, Republic of Korea.
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9
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Okkels N, Grothe MJ, Taylor JP, Hasselbalch SG, Fedorova TD, Knudsen K, van der Zee S, van Laar T, Bohnen NI, Borghammer P, Horsager J. Cholinergic changes in Lewy body disease: implications for presentation, progression and subtypes. Brain 2024; 147:2308-2324. [PMID: 38437860 DOI: 10.1093/brain/awae069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/05/2024] [Accepted: 02/13/2024] [Indexed: 03/06/2024] Open
Abstract
Cholinergic degeneration is significant in Lewy body disease, including Parkinson's disease, dementia with Lewy bodies, and isolated REM sleep behaviour disorder. Extensive research has demonstrated cholinergic alterations in the CNS of these disorders. More recently, studies have revealed cholinergic denervation in organs that receive parasympathetic denervation. This enables a comprehensive review of cholinergic changes in Lewy body disease, encompassing both central and peripheral regions, various disease stages and diagnostic categories. Across studies, brain regions affected in Lewy body dementia show equal or greater levels of cholinergic impairment compared to the brain regions affected in Lewy body disease without dementia. This observation suggests a continuum of cholinergic alterations between these disorders. Patients without dementia exhibit relative sparing of limbic regions, whereas occipital and superior temporal regions appear to be affected to a similar extent in patients with and without dementia. This implies that posterior cholinergic cell groups in the basal forebrain are affected in the early stages of Lewy body disorders, while more anterior regions are typically affected later in the disease progression. The topographical changes observed in patients affected by comorbid Alzheimer pathology may reflect a combination of changes seen in pure forms of Lewy body disease and those seen in Alzheimer's disease. This suggests that Alzheimer co-pathology is important to understand cholinergic degeneration in Lewy body disease. Thalamic cholinergic innervation is more affected in Lewy body patients with dementia compared to those without dementia, and this may contribute to the distinct clinical presentations observed in these groups. In patients with Alzheimer's disease, the thalamus is variably affected, suggesting a different sequential involvement of cholinergic cell groups in Alzheimer's disease compared to Lewy body disease. Patients with isolated REM sleep behaviour disorder demonstrate cholinergic denervation in abdominal organs that receive parasympathetic innervation from the dorsal motor nucleus of the vagus, similar to patients who experienced this sleep disorder in their prodrome. This implies that REM sleep behaviour disorder is important for understanding peripheral cholinergic changes in both prodromal and manifest phases of Lewy body disease. In conclusion, cholinergic changes in Lewy body disease carry implications for understanding phenotypes and the influence of Alzheimer co-pathology, delineating subtypes and pathological spreading routes, and for developing tailored treatments targeting the cholinergic system.
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Affiliation(s)
- Niels Okkels
- Department of Neurology, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Michel J Grothe
- Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Reina Sofia Alzheimer's Centre, CIEN Foundation-ISCIII, 28031 Madrid, Spain
| | - John-Paul Taylor
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Steen Gregers Hasselbalch
- Danish Dementia Research Center, Department of Neurology, Copenhagen University Hospital, 2100 Copenhagen Ø, Denmark
- Department of Clinical Medicine, University of Copenhagen, 2100 Copenhagen Ø, Denmark
| | - Tatyana D Fedorova
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Karoline Knudsen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Sygrid van der Zee
- Department of Neurology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Teus van Laar
- Department of Neurology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Nicolaas I Bohnen
- Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA
- Neurology Service and GRECC, VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
- Morris K. Udall Center of Excellence for Parkinson's Disease Research, University of Michigan, Ann Arbor, MI 48109, USA
- Parkinson's Foundation Research Center of Excellence, University of Michigan, Ann Arbor, MI 48109, USA
| | - Per Borghammer
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
| | - Jacob Horsager
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
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10
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Hazart D, Rolli-Derkinderen M, Delhomme B, Derkinderen P, Oheim M, Ricard C. [The gut, a whistleblower, in the early stages of Parkinson's disease]. Med Sci (Paris) 2024; 40:544-549. [PMID: 38986099 DOI: 10.1051/medsci/2024082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024] Open
Abstract
The enteric nervous system (ENS), often called the "second brain", plays a crucial role in regulating digestive functions. Dysfunctions of the ENS are associated with several diseases such as Parkinson's disease. Recent studies suggest that early digestive disorders, notably chronic constipation, may be early signs of this neurodegenerative disease. Three-dimensional imaging of the ENS offers new insights into early diagnosis, in particular through the analysis of intestinal biopsies. This new research axis raises questions about the intestinal cause of Parkinson's disease, and opens the door to a better understanding and earlier treatment of this disease.
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Affiliation(s)
- Doriane Hazart
- Université Paris Cité, SPPIN (Saint-Pères Paris Institute for the Neurosciences), CNRS UMR 8003, Paris, France
| | - Malvyne Rolli-Derkinderen
- Nantes Université, Inserm U1235, TENSGBD (The enteric nervous system in gut and brain disorders), Nantes, France
| | - Brigitte Delhomme
- Université Paris Cité, SPPIN (Saint-Pères Paris Institute for the Neurosciences), CNRS UMR 8003, Paris, France
| | - Pascal Derkinderen
- CHU Nantes, Nantes Université, TENSGBD (The enteric nervous system in gut and brain disorders), Nantes, France
| | - Martin Oheim
- Université Paris Cité, SPPIN (Saint-Pères Paris Institute for the Neurosciences), CNRS UMR 8003, Paris, France
| | - Clément Ricard
- Université Paris Cité, SPPIN (Saint-Pères Paris Institute for the Neurosciences), CNRS UMR 8003, Paris, France
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11
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Pellegrini C, Travagli RA. Gastrointestinal dysmotility in rodent models of Parkinson's disease. Am J Physiol Gastrointest Liver Physiol 2024; 326:G345-G359. [PMID: 38261717 PMCID: PMC11212145 DOI: 10.1152/ajpgi.00225.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/09/2024] [Accepted: 01/22/2024] [Indexed: 01/25/2024]
Abstract
Multiple studies describe prodromal, nonmotor dysfunctions that affect the quality of life of patients who subsequently develop Parkinson's disease (PD). These prodromal dysfunctions comprise a wide array of autonomic issues, including severe gastrointestinal (GI) motility disorders such as dysphagia, delayed gastric emptying, and chronic constipation. Indeed, strong evidence from studies in humans and animal models suggests that the GI tract and its neural, mainly vagal, connection to the central nervous system (CNS) could have a major role in the etiology of PD. In fact, misfolded α-synuclein aggregates that form Lewy bodies and neurites, i.e., the histological hallmarks of PD, are detected in the enteric nervous system (ENS) before clinical diagnosis of PD. The aim of the present review is to provide novel insights into the pathogenesis of GI dysmotility in PD, focusing our attention on functional, neurochemical, and molecular alterations in animal models.
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Affiliation(s)
- Carolina Pellegrini
- Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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12
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Thomasi B, Valdetaro L, Gulbransen B, Tavares-Gomes AL. Neuroimmune Connectomes in the Gut and Their Implications in Parkinson's Disease. Mol Neurobiol 2024; 61:2081-2098. [PMID: 37840070 PMCID: PMC11151216 DOI: 10.1007/s12035-023-03679-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/28/2023] [Indexed: 10/17/2023]
Abstract
The gastrointestinal tract is the largest immune organ and it receives dense innervation from intrinsic (enteric) and extrinsic (sympathetic, parasympathetic, and somatosensory) neurons. The immune and neural systems of the gut communicate with each other and their interactions shape gut defensive mechanisms and neural-controlled gut functions such as motility and secretion. Changes in neuroimmune interactions play central roles in the pathogenesis of diseases such as Parkinson's disease (PD), which is a multicentric disorder that is heterogeneous in its manifestation and pathogenesis. Non-motor and premotor symptoms of PD are common in the gastrointestinal tract and the gut is considered a potential initiation site for PD in some cases. How the enteric nervous system and neuroimmune signaling contribute to PD disease progression is an emerging area of interest. This review focuses on intestinal neuroimmune loops such as the neuroepithelial unit, enteric glial cells and their immunomodulatory effects, anti-inflammatory cholinergic signaling and the relationship between myenteric neurons and muscularis macrophages, and the role of α-synuclein in gut immunity. Special consideration is given to the discussion of intestinal neuroimmune connectomes during PD and their possible implications for various aspects of the disease.
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Affiliation(s)
- Beatriz Thomasi
- Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building - Gulbransen lab, 567, Wilson Rd, Room 3199, East Lansing, MI, USA.
| | - Luisa Valdetaro
- Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, USA
| | - Brian Gulbransen
- Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building - Gulbransen lab, 567, Wilson Rd, Room 3199, East Lansing, MI, USA
| | - Ana Lúcia Tavares-Gomes
- Programa de Pós-Graduação Em Neurociências, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
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13
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Okkels N, Horsager J, Fedorova TD, Knudsen K, Skjærbæk C, Andersen KB, Labrador-Espinosa M, Vestergaard K, Mortensen JK, Klit H, Møller M, Danielsen EH, Johnsen EL, Bekan G, Hansen KV, Munk OL, Damholdt MF, Kjeldsen PL, Hansen AK, Gottrup H, Grothe MJ, Borghammer P. Impaired cholinergic integrity of the colon and pancreas in dementia with Lewy bodies. Brain 2024; 147:255-266. [PMID: 37975822 DOI: 10.1093/brain/awad391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/20/2023] [Accepted: 10/28/2023] [Indexed: 11/19/2023] Open
Abstract
Dementia with Lewy bodies is characterized by a high burden of autonomic dysfunction and Lewy pathology in peripheral organs and components of the sympathetic and parasympathetic nervous system. Parasympathetic terminals may be quantified with 18F-fluoroetoxybenzovesamicol, a PET tracer that binds to the vesicular acetylcholine transporter in cholinergic presynaptic terminals. Parasympathetic imaging may be useful for diagnostics, improving our understanding of autonomic dysfunction and for clarifying the spatiotemporal relationship of neuronal degeneration in prodromal disease. Therefore, we aimed to investigate the cholinergic parasympathetic integrity in peripheral organs and central autonomic regions of subjects with dementia with Lewy bodies and its association with subjective and objective measures of autonomic dysfunction. We hypothesized that organs with known parasympathetic innervation, especially the pancreas and colon, would have impaired cholinergic integrity. To achieve these aims, we conducted a cross-sectional comparison study including 23 newly diagnosed non-diabetic subjects with dementia with Lewy bodies (74 ± 6 years, 83% male) and 21 elderly control subjects (74 ± 6 years, 67% male). We obtained whole-body images to quantify PET uptake in peripheral organs and brain images to quantify PET uptake in regions of the brainstem and hypothalamus. Autonomic dysfunction was assessed with questionnaires and measurements of orthostatic blood pressure. Subjects with dementia with Lewy bodies displayed reduced cholinergic tracer uptake in the pancreas (32% reduction, P = 0.0003) and colon (19% reduction, P = 0.0048), but not in organs with little or no parasympathetic innervation. Tracer uptake in a region of the medulla oblongata overlapping the dorsal motor nucleus of the vagus correlated with autonomic symptoms (rs = -0.54, P = 0.0077) and changes in orthostatic blood pressure (rs = 0.76, P < 0.0001). Tracer uptake in the pedunculopontine region correlated with autonomic symptoms (rs = -0.52, P = 0.0104) and a measure of non-motor symptoms (rs = -0.47, P = 0.0230). In conclusion, our findings provide the first imaging-based evidence of impaired cholinergic integrity of the pancreas and colon in dementia with Lewy bodies. The observed changes may reflect parasympathetic denervation, implying that this process is initiated well before the point of diagnosis. The findings also support that cholinergic denervation in the brainstem contributes to dysautonomia.
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Affiliation(s)
- Niels Okkels
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
- Department of Neurology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Jacob Horsager
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Tatyana D Fedorova
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Karoline Knudsen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Casper Skjærbæk
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Katrine B Andersen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Miguel Labrador-Espinosa
- Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | | | - Janne K Mortensen
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
- Department of Neurology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Henriette Klit
- Department of Neurology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Mette Møller
- Department of Neurology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Erik H Danielsen
- Department of Neurology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Erik L Johnsen
- Department of Neurology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Goran Bekan
- Department of Neurology, Regionshospitalet Gødstrup, 7400 Herning, Denmark
| | - Kim V Hansen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Ole L Munk
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Malene F Damholdt
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
| | - Pernille L Kjeldsen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
- Department of Neurology, Aalborg University Hospital, 9000 Aalborg, Denmark
| | - Allan K Hansen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Nuclear Medicine, Aalborg University Hospital, 9000 Aalborg, Denmark
| | - Hanne Gottrup
- Department of Neurology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Michel J Grothe
- Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Per Borghammer
- Department of Nuclear Medicine and PET, Aarhus University Hospital, 8200 Aarhus N, Denmark
- Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
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14
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Chandra R, Sokratian A, Chavez KR, King S, Swain SM, Snyder JC, West AB, Liddle RA. Gut mucosal cells transfer α-synuclein to the vagus nerve. JCI Insight 2023; 8:e172192. [PMID: 38063197 PMCID: PMC10795834 DOI: 10.1172/jci.insight.172192] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 10/27/2023] [Indexed: 12/18/2023] Open
Abstract
Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease. Although past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut-to-brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of intestinal mucosa express α-synuclein. Here, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from epithelial cells in organoids to cocultured nodose neurons devoid of α-synuclein. In mice expressing human α-synuclein, but no mouse α-synuclein, α-synuclein fibril-templating activity emerged in α-synuclein-seeded fibril aggregation assays in intestine, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfered to the vagus nerve and dorsal motor nucleus. Subdiaphragmatic vagotomy prior to induction of α-synuclein expression in intestinal epithelial cells effectively protected the hindbrain from emergence of α-synuclein fibril-templating activity. Overall, these findings highlight a potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.
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Affiliation(s)
| | | | | | | | | | - Joshua C. Snyder
- Department of Surgery, and
- Department of Cell Biology, Duke University, Durham, North Carolina, USA
| | - Andrew B. West
- Department of Pharmacology and Cancer Biology
- Duke Institute for Brain Sciences, Durham, North Carolina, USA
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA
| | - Rodger A. Liddle
- Department of Medicine
- Duke Institute for Brain Sciences, Durham, North Carolina, USA
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA
- Department of Veterans Affairs, Chevy Chase, Maryland, USA
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15
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Garretti F, Monahan C, Sloan N, Bergen J, Shahriar S, Kim SW, Sette A, Cutforth T, Kanter E, Agalliu D, Sulzer D. Interaction of an α-synuclein epitope with HLA-DRB1 ∗15:01 triggers enteric features in mice reminiscent of prodromal Parkinson's disease. Neuron 2023; 111:3397-3413.e5. [PMID: 37597517 PMCID: PMC11068096 DOI: 10.1016/j.neuron.2023.07.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 06/07/2023] [Accepted: 07/24/2023] [Indexed: 08/21/2023]
Abstract
Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein (α-syn)-derived epitopes. One epitope, α-syn32-46, binds with strong affinity to the HLA-DRB1∗15:01 allele implicated in autoimmune diseases. We report that α-syn32-46 immunization in a mouse expressing human HLA-DRB1∗15:01 triggers intestinal inflammation, leading to loss of enteric neurons, damaged enteric dopaminergic neurons, constipation, and weight loss. α-Syn32-46 immunization activates innate and adaptive immune gene signatures in the gut and induces changes in the CD4+ TH1/TH17 transcriptome that resemble tissue-resident memory (TRM) cells found in mucosal barriers during inflammation. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn32-46 and HLA-DRB1∗15:0 is critical for gut inflammation and CD4+ T cell-mediated loss of enteric neurons in humanized mice, suggesting mechanisms that may underlie prodromal enteric PD.
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Affiliation(s)
- Francesca Garretti
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA; Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Connor Monahan
- Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Nicholas Sloan
- Department of Neuroscience, Columbia University, New York, NY, USA
| | - Jamie Bergen
- Department of Neuroscience, Columbia University, New York, NY, USA; Department of Computer Science, Columbia University, New York, NY, USA
| | - Sanjid Shahriar
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Seon Woo Kim
- Weill Cornell Medicine - Qatar, Education City, Doha, Qatar
| | - Alessandro Sette
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Medicine, University of California in San Diego, San Diego, CA, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Tyler Cutforth
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
| | - Ellen Kanter
- Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Dritan Agalliu
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
| | - David Sulzer
- Departments of Psychiatry and Pharmacology, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
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16
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Chandra R, Sokratian A, Chavez KR, King S, Swain SM, Snyder JC, West AB, Liddle RA. Gut mucosal cells transfer α-synuclein to the vagus nerve. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.14.553305. [PMID: 37645945 PMCID: PMC10461984 DOI: 10.1101/2023.08.14.553305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.
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17
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Quigley EMM. Constipation in Parkinson's Disease. Semin Neurol 2023; 43:562-571. [PMID: 37579786 DOI: 10.1055/s-0043-1771457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2023]
Abstract
Constipation is one of the most common gastrointestinal features of Parkinson's disease (PD), occurring in over 50% of all PD patients during the course of their disease. Furthermore, constipation is now recognized as an important, prodromal symptom and may predate the onset of the classical motor symptoms by decades. Thereafter, the prevalence and severity of constipation in PD tend to parallel the course of both motor and nonmotor phenomena such as cognitive decline and depression. Difficult defecation (obstructed defecation, dyssynergia) is the primary pathophysiology underlying constipation and likely reflects involvement by the PD process of one or more of the many skeletal muscle groups that are involved in effecting defecation. Management of constipation in PD may be complicated by several patient factors including dysphagia, cognitive impairment, depression, and weak sphincter tone. While the armamentarium available to those who treat constipation, in general, has expanded considerably in recent years, the evidence supporting any therapy in the management of this symptom in PD has remained slim.
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Affiliation(s)
- Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, Texas
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18
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Borghammer P. The brain-first vs. body-first model of Parkinson's disease with comparison to alternative models. J Neural Transm (Vienna) 2023; 130:737-753. [PMID: 37062013 DOI: 10.1007/s00702-023-02633-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/03/2023] [Indexed: 04/17/2023]
Abstract
The ultimate origin of Lewy body disorders, including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), is still incompletely understood. Although a large number of pathogenic mechanisms have been implicated, accumulating evidence support that aggregation and neuron-to-neuron propagation of alpha-synuclein may be the core feature of these disorders. The synuclein, origin, and connectome (SOC) disease model of Lewy body disorders was recently introduced. This model is based on the hypothesis that in the majority of patients, the first alpha-synuclein pathology arises in single location and spreads from there. The most common origin sites are the enteric nervous system and the olfactory system. The SOC model predicts that gut-first pathology leads to a clinical body-first subtype characterized by prodromal autonomic symptoms and REM sleep behavior disorder. In contrast, olfactory-first pathology leads to a brain-first subtype with fewer non-motor symptoms before diagnosis. The SOC model further predicts that body-first patients are older, more commonly develop symmetric dopaminergic degeneration, and are at increased risk of dementia-compared to brain-first patients. In this review, the SOC model is explained and compared to alternative models of the pathogenesis of Lewy body disorders, including the Braak staging system, and the Unified Staging System for Lewy Body Disorders. Postmortem evidence from brain banks and clinical imaging data of dopaminergic and cardiac sympathetic loss is reviewed. It is concluded that these datasets seem to be more compatible with the SOC model than with those alternative disease models of Lewy body disorders.
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Affiliation(s)
- Per Borghammer
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Palle Juul-Jensens Boulevard 165, J220, 8200, Aarhus, Denmark.
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19
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López-Pingarrón L, Almeida H, Soria-Aznar M, Reyes-Gonzales MC, Rodríguez-Moratinos AB, Muñoz-Hoyos A, García JJ. Interstitial Cells of Cajal and Enteric Nervous System in Gastrointestinal and Neurological Pathology, Relation to Oxidative Stress. Curr Issues Mol Biol 2023; 45:3552-3572. [PMID: 37185756 PMCID: PMC10136929 DOI: 10.3390/cimb45040232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/16/2023] [Accepted: 04/17/2023] [Indexed: 05/17/2023] Open
Abstract
The enteric nervous system (ENS) is organized into two plexuses-submucosal and myenteric-which regulate smooth muscle contraction, secretion, and blood flow along the gastrointestinal tract under the influence of the rest of the autonomic nervous system (ANS). Interstitial cells of Cajal (ICCs) are mainly located in the submucosa between the two muscle layers and at the intramuscular level. They communicate with neurons of the enteric nerve plexuses and smooth muscle fibers and generate slow waves that contribute to the control of gastrointestinal motility. They are also involved in enteric neurotransmission and exhibit mechanoreceptor activity. A close relationship appears to exist between oxidative stress and gastrointestinal diseases, in which ICCs can play a prominent role. Thus, gastrointestinal motility disorders in patients with neurological diseases may have a common ENS and central nervous system (CNS) nexus. In fact, the deleterious effects of free radicals could affect the fine interactions between ICCs and the ENS, as well as between the ENS and the CNS. In this review, we discuss possible disturbances in enteric neurotransmission and ICC function that may cause anomalous motility in the gut.
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Affiliation(s)
- Laura López-Pingarrón
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Henrique Almeida
- i3S-Instituto de Investigação e Inovação em Saúde, Porto University, 4200-135 Porto, Portugal
- Department of Biomedicine, Faculty of Medicine, Porto University, 4200-319 Porto, Portugal
- Department of Obstetrics and Gynecology, Hospital-CUF Porto, 4100-180 Porto, Portugal
| | - Marisol Soria-Aznar
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - Marcos C Reyes-Gonzales
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | | | - Antonio Muñoz-Hoyos
- Department of Pediatrics, Faculty of Medicine, University of Granada, 18016 Granada, Spain
| | - Joaquín J García
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain
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20
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Chen M, Mor DE. Gut-to-Brain α-Synuclein Transmission in Parkinson's Disease: Evidence for Prion-like Mechanisms. Int J Mol Sci 2023; 24:ijms24087205. [PMID: 37108366 PMCID: PMC10139032 DOI: 10.3390/ijms24087205] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
Parkinson's disease (PD) is a multifactorial disorder involving both motor and non-motor symptoms caused by the progressive death of distinct neuronal populations, including dopaminergic neurons in the substantia nigra. The deposition of aggregated α-synuclein protein into Lewy body inclusions is a hallmark of the disorder, and α-synuclein pathology has been found in the enteric nervous system (ENS) of PD patients up to two decades prior to diagnosis. In combination with the high occurrence of gastrointestinal dysfunction in early stages of PD, current evidence strongly suggests that some forms of PD may originate in the gut. In this review, we discuss human studies that support ENS Lewy pathology as a characteristic feature of PD, and present evidence from humans and animal model systems that α-synuclein aggregation may follow a prion-like spreading cascade from enteric neurons, through the vagal nerve, and into the brain. Given the accessibility of the human gut to pharmacologic and dietary interventions, therapeutic strategies aimed at reducing pathological α-synuclein in the gastrointestinal tract hold significant promise for PD treatment.
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Affiliation(s)
- Merry Chen
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Danielle E Mor
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
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21
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Abstract
Abnormalities in gut microbiota have been suggested to be involved in the pathophysiology and progression of Parkinson's disease (PD). Gastrointestinal nonmotor symptoms often precede the onset of motor features in PD, suggesting a role for gut dysbiosis in neuroinflammation and α-synuclein (α-syn) aggregation. In the first part of this chapter, we analyze critical features of healthy gut microbiota and factors (environmental and genetic) that modify its composition. In the second part, we focus on the mechanisms underlying the gut dysbiosis and how it alters anatomically and functionally the mucosal barrier, triggering neuroinflammation and subsequently α-syn aggregation. In the third part, we describe the most common alterations in the gut microbiota of PD patients, dividing the gastrointestinal system in higher and lower tract to examine the association between microbiota abnormalities and clinical features. In the final section, we report on current and future therapeutic approaches to gut dysbiosis aiming to either reduce the risk for PD, modify the disease course, or improve the pharmacokinetic profile of dopaminergic therapies. We also suggest that further studies will be needed to clarify the role of the microbiome in PD subtyping and of pharmacological and nonpharmacological interventions in modifying specific microbiota profiles in individualizing disease-modifying treatments in PD.
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Affiliation(s)
- Salvatore Bonvegna
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Clinical Neurosciences, Parkinson and Movement Disorders Unit, Milan, Italy
| | - Roberto Cilia
- Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Clinical Neurosciences, Parkinson and Movement Disorders Unit, Milan, Italy.
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22
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Camilleri M, Subramanian T, Pagan F, Isaacson S, Gil R, Hauser RA, Feldman M, Goldstein M, Kumar R, Truong D, Chhabria N, Walter BL, Eskenazi J, Riesenberg R, Burdick D, Tse W, Molho E, Robottom B, Bhatia P, Kadimi S, Klos K, Shprecher D, Marquez-Mendoza O, Hidalgo G, Grill S, Li G, Mandell H, Hughes M, Stephenson S, Vandersluis J, Pfeffer M, Duker A, Shivkumar V, Kinney W, MacDougall J, Zasloff M, Barbut D. Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial. Ann Intern Med 2022; 175:1666-1674. [PMID: 36343348 DOI: 10.7326/m22-1438] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. OBJECTIVE To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. DESIGN Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791). SETTING Outpatient. PATIENTS 150 patients with PD and constipation. INTERVENTION ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. MEASUREMENTS The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). RESULTS The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). LIMITATION Longer treatment periods need to be investigated in future studies. CONCLUSION ENT-01 was safe and significantly improved constipation. PRIMARY FUNDING SOURCE Enterin, Inc.
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Affiliation(s)
| | | | - Fernando Pagan
- Department of Neurology, Georgetown University Hospital, Washington, DC (F.P.)
| | - Stuart Isaacson
- Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, Florida (S.I.)
| | - Ramon Gil
- Parkinson's Disease Treatment Center of SW Florida, Port Charlotte, Florida (R.G.)
| | - Robert A Hauser
- USF Parkinson's Disease and Movement Disorder Center, Tampa, Florida (R.A.H.)
| | - Mary Feldman
- Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire (M.F.)
| | - Mark Goldstein
- JEM Headlands Research Institute, Atlantis, Florida (M.G.)
| | - Rajeev Kumar
- Rocky Mountain Movement Disorder Center, Englewood, Colorado (R.K.)
| | - Daniel Truong
- The Parkinson's and Movement Disorder Institute, Fountain Valley, California (D.T.)
| | - Nisha Chhabria
- Palm Beach Neurology and Premiere Research Institute, West Palm Beach, Florida (N.C.)
| | - Benjamin L Walter
- Parkinson's and Movement Disorders Center, Cleveland Clinic, Cleveland, Ohio (B.L.W.)
| | | | | | - Daniel Burdick
- Booth Gardner Parkinson's Care Center, EvergreenHealth, Kirkland, Washington (D.B.)
| | - Winona Tse
- Parkinson's and Movement Disorders Center, Icahn School of Medicine at Mount Sinai, New York, New York (W.T.)
| | - Eric Molho
- Parkinson's Disease and Movement Center, Albany Medical College, Albany, New York (E.M.)
| | | | | | - Srinath Kadimi
- Associated Neurologists of Southern Connecticut, Fairfield, Connecticut (S.K.)
| | - Kevin Klos
- The Movement Disorder Clinic of Oklahoma, Tulsa, Oklahoma (K.K.)
| | - David Shprecher
- Banner Sun Health Research Institute, Sun City, Arizona (D.S.)
| | | | - Gonzalo Hidalgo
- The Neuromedical Clinic of Central Louisiana, Alexandria, Louisiana (G.H.)
| | - Stephen Grill
- Parkinson's and Movement Disorders Center of Maryland, Elkridge, Maryland (S.G.)
| | - George Li
- MEDSOL Clinical Research, Port Charlotte, Florida (G.L.)
| | - Howard Mandell
- Metrolina Neurological Associates, Indian Land, South Carolina (H.M.)
| | - Mary Hughes
- Premier Neurology, Greer, South Carolina (M.H.)
| | | | - Joel Vandersluis
- Elias Research, Neurology Diagnostics, Inc., Dayton, Ohio (J.V.)
| | - Michael Pfeffer
- Allied Biomedical Neurologic Research Institute, Miami, Florida (M.P.)
| | - Andrew Duker
- University of Cincinnati, Cincinnati, Ohio (A.D.)
| | - Vikram Shivkumar
- University Physicians and Surgeons, Inc., Marshall Health, Huntington, West Virginia (V.S.)
| | | | - James MacDougall
- MacDougall Statistical Institute, Haverhill, Massachusetts (J.M.)
| | - Michael Zasloff
- Medstar-Georgetown Transplant Institute, Washington, DC, and Enterin Research Institute and Enterin, Inc., Philadelphia, Pennsylvania (M.Z.)
| | - Denise Barbut
- Enterin Research Institute and Enterin, Inc., Philadelphia, Pennsylvania (D.B.)
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23
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Horsager J, Okkels N, Fedorova TD, Knudsen K, Skjærbæk C, Van Den Berge N, Jacobsen J, Munk OL, Danielsen EH, Bender D, Brooks DJ, Borghammer P. [ 18F]FEOBV positron emission tomography may not be a suitable method to measure parasympathetic denervation in patients with Parkinson's disease. Parkinsonism Relat Disord 2022; 104:21-25. [PMID: 36198248 DOI: 10.1016/j.parkreldis.2022.09.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/22/2022] [Accepted: 09/25/2022] [Indexed: 01/09/2023]
Abstract
INTRODUCTION The peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [18F]FEOBV uptake in peripheral organs - a sign of parasympathetic denervation. METHODS We included 15 PD patients and 15 age- and sex matched healthy controls for a 70 min whole-body dynamic positron emission tomography (PET) acquisition. Compartmental modelling was used for tracer kinetic analyses of adrenal gland, pancreas, myocardium, spleen, renal cortex, muscle and colon. Standard uptake values (SUV) at 60-70 min post injection were also extracted for these organs. Additionally, SUVs were also determined in the total colon, prostate, parotid and submandibular glands. RESULTS We found no statistically significant difference of [18F]FEOBV binding parameters in any organs between patients with PD and healthy controls, although trends were observed. The pancreas SUV showed a 14% reduction in patients (P = 0.021, not statistically significant after multiple comparison correction). We observed a trend towards lower SUVs in the pancreas, colon, adrenal gland, and myocardium of PD patients with versus without probable REM sleep behavior disorder. CONCLUSION [18F]FEOBV PET may not be a sensitive marker for parasympathetic degeneration in patients with PD.
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Affiliation(s)
- Jacob Horsager
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Niels Okkels
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
| | - Tatyana D Fedorova
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Karoline Knudsen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
| | - Casper Skjærbæk
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
| | - Nathalie Van Den Berge
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jan Jacobsen
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
| | - Ole Lajord Munk
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
| | | | - Dirk Bender
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
| | - David J Brooks
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark; Institute of Translational and Clinical Research, University of Newcastle Upon Tyne, UK
| | - Per Borghammer
- Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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24
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Liu Y, Wang W, Song N, Jiao L, Jia F, Du X, Chen X, Yan C, Jiao J, Jiao Q, Jiang H. Ghrelin Bridges DMV Neuropathology and GI Dysfunction in the Early Stages of Parkinson's Disease. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2203020. [PMID: 36050877 PMCID: PMC9596842 DOI: 10.1002/advs.202203020] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/04/2022] [Indexed: 06/15/2023]
Abstract
Ghrelin contributes to the communication between the brain and gastrointestinal (GI) tract. Both decreased ghrelin levels and functional GI disorders are early events in Parkinson's disease (PD) patients and animal models. However, the reason is not clear. Here it is found that choline acetyltransferase (ChAT)-positive neurons in the dorsal motor nucleus of the vagus nerve (DMV), are lost in PD transgenic mice. In response to the selective damaging of DMV neurons with mu p75-SAP, a rapid reduction both in plasma total and active ghrelin levels is observed. While by contrast, chemogenetic activation of DMV cholinergic neurons can increase the plasma ghrelin levels. Impairment of cholinergic neurons is accompanied by GI disorders, including decreased stool wet weight, stool dry weight, small intestine advancing rate, and gastric emptying rate, while exogenous ghrelin treatment can partially ameliorate GI dysfunction of A53T α-synuclein transgenic mice. Using pseudorabies virus retrograde trace method, the existence of a direct pathway from the stomach fundus to the DMV is shown. Taken together, the findings suggest that the reduction in plasma ghrelin levels in the early stages of PD may be the result of the lesion of cholinergic neurons in the DMV, thus linking neurodegeneration and GI dysfunction in PD.
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Affiliation(s)
- Yizhen Liu
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Weiwei Wang
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Ning Song
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Lingling Jiao
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Fengju Jia
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Xixun Du
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Xi Chen
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Chunling Yan
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Jianwei Jiao
- State Key Laboratory of Stem Cell and Reproductive BiologyInstitute of ZoologyChinese Academy of SciencesBeijing100101China
| | - Qian Jiao
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
| | - Hong Jiang
- Department of PhysiologyShandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic MedicineQingdao UniversityQingdaoShandong710061China
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25
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Manfready RA, Goetz CG, Keshavarzian A. Intestinal microbiota and neuroinflammation in Parkinson's disease: At the helm of the gut-brain axis. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 167:81-99. [PMID: 36427960 DOI: 10.1016/bs.irn.2022.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Emerging data suggest that disrupted intestinal microbiota, or dysbiosis, may be responsible for multiple features of Parkinson's disease (PD), from initiation, to progression, to therapeutic response. We have progressed greatly in our understanding of microbial signatures associated with PD, and have gained important insights into how dysbiosis and intestinal permeability promote neurodegeneration through neuroinflammation and Lewy body formation. These insights underscore the potential of microbiota-directed therapies, which include dietary, pharmacologic, and lifestyle interventions.
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Affiliation(s)
- Richard A Manfready
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, United States
| | - Christopher G Goetz
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
| | - Ali Keshavarzian
- Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, United States; Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States.
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26
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Poirier AA, Côté M, Jarras H, Litim N, Lamontagne-Proulx J, Al-Sweidi S, Morissette M, Lachhab A, Pelletier M, Di Paolo T, Soulet D. Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson's Disease Models. Front Pharmacol 2022; 13:898067. [PMID: 35935876 PMCID: PMC9355275 DOI: 10.3389/fphar.2022.898067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/27/2022] [Indexed: 11/21/2022] Open
Abstract
Gastrointestinal disorders in Parkinson's disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.
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Affiliation(s)
- Andrée-Anne Poirier
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec City, QC, Canada
| | - Mélissa Côté
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
| | - Hend Jarras
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec City, QC, Canada
| | - Nadhir Litim
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec City, QC, Canada
| | - Jérôme Lamontagne-Proulx
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec City, QC, Canada
| | - Sara Al-Sweidi
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec City, QC, Canada
| | - Marc Morissette
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
| | - Asmaa Lachhab
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Martin Pelletier
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Médecine, Université Laval, Québec City, QC, Canada
| | - Thérèse Di Paolo
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec City, QC, Canada
| | - Denis Soulet
- Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec City, QC, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Université Laval, Québec City, QC, Canada
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27
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Tan AH, Lim SY, Lang AE. The microbiome-gut-brain axis in Parkinson disease - from basic research to the clinic. Nat Rev Neurol 2022; 18:476-495. [PMID: 35750883 DOI: 10.1038/s41582-022-00681-2] [Citation(s) in RCA: 168] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2022] [Indexed: 12/12/2022]
Abstract
Evidence for a close bidirectional link between the brain and the gut has led to a paradigm shift in neurology, especially in the case of Parkinson disease (PD), in which gastrointestinal dysfunction is a prominent feature. Over the past decade, numerous high-quality preclinical and clinical publications have shed light on the highly complex relationship between the gut and the brain in PD, providing potential for the development of new biomarkers and therapeutics. With the advent of high-throughput sequencing, the role of the gut microbiome has been specifically highlighted. Here, we provide a critical review of the literature on the microbiome-gut-brain axis in PD and present perspectives that will be useful for clinical practice. We begin with an overview of the gut-brain axis in PD, including the potential roles and interrelationships of the vagus nerve, α-synuclein in the enteric nervous system, altered intestinal permeability and inflammation, and gut microbes and their metabolic activities. The sections that follow synthesize the proposed roles of gut-related factors in the development and progression of, in responses to PD treatment, and as therapeutic targets. Finally, we summarize current knowledge gaps and challenges and delineate future directions for the field.
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Affiliation(s)
- Ai Huey Tan
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. .,Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
| | - Shen Yang Lim
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.,Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Anthony E Lang
- Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Ontario, Canada.,Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
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28
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Yang R, Gao G, Yang H. The Pathological Mechanism Between the Intestine and Brain in the Early Stage of Parkinson's Disease. Front Aging Neurosci 2022; 14:861035. [PMID: 35813958 PMCID: PMC9263383 DOI: 10.3389/fnagi.2022.861035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 06/02/2022] [Indexed: 11/13/2022] Open
Abstract
Parkinson's disease (PD) is the second most common chronic progressive neurodegenerative disease. The main pathological features are progressive degeneration of neurons and abnormal accumulation of α-synuclein. At present, the pathogenesis of PD is not completely clear, and many changes in the intestinal tract may be the early pathogenic factors of PD. These changes affect the central nervous system (CNS) through both nervous and humoral pathways. α-Synuclein deposited in the intestinal nerve migrates upward along the vagus nerve to the brain. Inflammation and immune regulation mediated by intestinal immune cells may be involved, affecting the CNS through local blood circulation. In addition, microorganisms and their metabolites may also affect the progression of PD. Therefore, paying attention to the multiple changes in the intestinal tract may provide new insight for the early diagnosis and treatment of PD.
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29
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Jotanovic J, Milin-Lazovic J, Alafuzoff I. Gastrointestinal Biopsy Obtained During Cancer Screening, a Biological Marker for α-Synucleinopathy? J Neuropathol Exp Neurol 2022; 81:356-362. [PMID: 35388426 PMCID: PMC9041339 DOI: 10.1093/jnen/nlac023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The hallmark alteration in α-synucleinopathies, α-synuclein, is observed not only in the brain but also in the peripheral tissues, particularly in the intestine. This suggests that endoscopic biopsies performed for colon cancer screening could facilitate the assessment of α-synuclein in the gastrointestinal (GI) tract. Using immunohistochemistry for α-synuclein, we assessed whether GI biopsies could be used to confirm an ongoing α-synucleinopathy. Seventy-four subjects with cerebral α-synucleinopathy in various Braak stages with concomitant GI biopsies were available for study. In 81% of the subjects, α-synuclein was seen in the mucosal/submucosal GI biopsies. Two subjects with severe cerebral α-synucleinopathy and a long delay between biopsy and death displayed no α-synuclein pathology in the gut, and 11 subjects with sparse cerebral α-synucleinopathy displayed GI α-synuclein up to 36 years prior to death. The finding that there was no GI α-synuclein in 19% of the subjects with cerebral α-synucleinopathy, and α-synuclein was observed in the gut of 11 subjects (15%) with sparse cerebral α-synucleinopathy even many years prior to death is unexpected and jeopardizes the use of assessment of α-synuclein in the peripheral tissue for confirmation of an ongoing cerebral α-synucleinopathy.
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Affiliation(s)
- Jelena Jotanovic
- Department of Pathology, Uppsala University Hospital, Uppsala, Sweden
| | - Jelena Milin-Lazovic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Irina Alafuzoff
- Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.,Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Neonatal 6-hydroxydopamine lesioning of rats and dopaminergic neurotoxicity: proposed animal model of Parkinson’s disease. J Neural Transm (Vienna) 2022; 129:445-461. [DOI: 10.1007/s00702-022-02479-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/11/2022] [Indexed: 10/18/2022]
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Han MN, Finkelstein DI, McQuade RM, Diwakarla S. Gastrointestinal Dysfunction in Parkinson’s Disease: Current and Potential Therapeutics. J Pers Med 2022; 12:jpm12020144. [PMID: 35207632 PMCID: PMC8875119 DOI: 10.3390/jpm12020144] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 02/04/2023] Open
Abstract
Abnormalities in the gastrointestinal (GI) tract of Parkinson’s disease (PD) sufferers were first reported over 200 years ago; however, the extent and role of GI dysfunction in PD disease progression is still unknown. GI dysfunctions, including dysphagia, gastroparesis, and constipation, are amongst the most prevalent non-motor symptoms in PD. These symptoms not only impact patient quality of life, but also complicate disease management. Conventional treatment pathways for GI dysfunctions (i.e., constipation), such as increasing fibre and fluid intake, and the use of over-the-counter laxatives, are generally ineffective in PD patients, and approved compounds such as guanylate cyclase C agonists and selective 5-hyroxytryptamine 4 receptor agonists have demonstrated limited efficacy. Thus, identification of potential targets for novel therapies to alleviate PD-induced GI dysfunctions are essential to improve clinical outcomes and quality of life in people with PD. Unlike the central nervous system (CNS), where PD pathology and the mechanisms involved in CNS damage are relatively well characterised, the effect of PD at the cellular and tissue level in the enteric nervous system (ENS) remains unclear, making it difficult to alleviate or reverse GI symptoms. However, the resurgence of interest in understanding how the GI tract is involved in various disease states, such as PD, has resulted in the identification of novel therapeutic avenues. This review focuses on common PD-related GI symptoms, and summarizes the current treatments available and their limitations. We propose that by targeting the intestinal barrier, ENS, and/or the gut microbiome, may prove successful in alleviating PD-related GI symptoms, and discuss emerging therapies and potential drugs that could be repurposed to target these areas.
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Affiliation(s)
- Myat Noe Han
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
| | - David I. Finkelstein
- Parkinson’s Disease Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia;
| | - Rachel M. McQuade
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
- Correspondence: ; Tel.: +61-3-8395-8114
| | - Shanti Diwakarla
- Gut-Axis Injury and Repair Laboratory, Department of Medicine Western Health, University of Melbourne, Melbourne, VIC 3021, Australia; (M.N.H.); (S.D.)
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
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O’Day C, Finkelstein DI, Diwakarla S, McQuade RM. A Critical Analysis of Intestinal Enteric Neuron Loss and Constipation in Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2022; 12:1841-1861. [PMID: 35848035 PMCID: PMC9535602 DOI: 10.3233/jpd-223262] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/26/2022] [Indexed: 06/06/2023]
Abstract
Constipation afflicts many patients with Parkinson's disease (PD) and significantly impacts on patient quality of life. PD-related constipation is caused by intestinal dysfunction, but the etiology of this dysfunction in patients is unknown. One possible cause is neuron loss within the enteric nervous system (ENS) of the intestine. This review aims to 1) Critically evaluate the evidence for and against intestinal enteric neuron loss in PD patients, 2) Justify why PD-related constipation must be objectively measured, 3) Explore the potential link between loss of enteric neurons in the intestine and constipation in PD, 4) Provide potential explanations for disparities in the literature, and 5) Outline data and study design considerations to improve future research. Before the connection between intestinal enteric neuron loss and PD-related constipation can be confidently described, future research must use sufficiently large samples representative of the patient population (majority diagnosed with idiopathic PD for at least 5 years), implement a consistent neuronal quantification method and study design, including standardized patient recruitment criteria, objectively quantify intestinal dysfunctions, publish with a high degree of data transparency and account for potential PD heterogeneity. Further investigation into other potential influencers of PD-related constipation is also required, including changes in the function, connectivity, mitochondria and/or α-synuclein proteins of enteric neurons and their extrinsic innervation. The connection between enteric neuron loss and other PD-related gastrointestinal (GI) issues, including gastroparesis and dysphagia, as well as changes in nutrient absorption and the microbiome, should be explored in future research.
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Affiliation(s)
- Chelsea O’Day
- Gut-Axis Injury & Repair Laboratory, Department of Medicine - Western Centre for Health Research and Education (WCHRE), The University of Melbourne, Sunshine Hospital, St Albans, VIC, Australia
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE) Level 3 and 4, Sunshine Hospital, St Albans, VIC, Australia
| | - David Isaac Finkelstein
- Parkinson’s Disease Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
| | - Shanti Diwakarla
- Gut-Axis Injury & Repair Laboratory, Department of Medicine - Western Centre for Health Research and Education (WCHRE), The University of Melbourne, Sunshine Hospital, St Albans, VIC, Australia
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE) Level 3 and 4, Sunshine Hospital, St Albans, VIC, Australia
| | - Rachel Mai McQuade
- Gut-Axis Injury & Repair Laboratory, Department of Medicine - Western Centre for Health Research and Education (WCHRE), The University of Melbourne, Sunshine Hospital, St Albans, VIC, Australia
- The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE) Level 3 and 4, Sunshine Hospital, St Albans, VIC, Australia
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Derkinderen P, Cossais F, de Guilhem de Lataillade A, Leclair-Visonneau L, Neunlist M, Paillusson S, De Giorgio R. Gastrointestinal mucosal biopsies in Parkinson's disease: beyond alpha-synuclein detection. J Neural Transm (Vienna) 2021; 129:1095-1103. [PMID: 34816335 DOI: 10.1007/s00702-021-02445-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 11/17/2021] [Indexed: 11/24/2022]
Abstract
Alpha-synuclein deposits, the pathological hallmarks of Parkinson's disease, are consistently found in the gastrointestinal tract of parkinsonian subjects. These observations have raised the potential that endoscopically obtainable mucosal biopsies can aid to a molecular diagnosis of the disease. The possible usefulness of mucosal biopsies is, however, not limited to the detection of alpha-synuclein, but also extends to other essential aspects underlying pathophysiological mechanisms of gastrointestinal manifestations in Parkinson's disease. The aim of the current review is to provide an appraisal of the existing studies showing that gastrointestinal biopsies can be used for the analysis of enteric neuronal and glial cell morphology, intestinal epithelial barrier function, and gastrointestinal inflammation in Parkinson's disease. A perspective on the generation of organoids with GI biopsies and the potential use of single-cell and spatial transcriptomic technologies will be also addressed.
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Affiliation(s)
- Pascal Derkinderen
- Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Inserm U1235 Nantes, Université de Nantes, 1 rue Gaston Veil, 44035, Nantes, France. .,Department of Neurology, CHU Nantes, 44093, Nantes, France.
| | | | - Adrien de Guilhem de Lataillade
- Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Inserm U1235 Nantes, Université de Nantes, 1 rue Gaston Veil, 44035, Nantes, France.,Department of Neurology, CHU Nantes, 44093, Nantes, France
| | - Laurène Leclair-Visonneau
- Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Inserm U1235 Nantes, Université de Nantes, 1 rue Gaston Veil, 44035, Nantes, France.,Department of Physiology, CHU Nantes, 44093, Nantes, France
| | - Michel Neunlist
- Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Inserm U1235 Nantes, Université de Nantes, 1 rue Gaston Veil, 44035, Nantes, France
| | - Sébastien Paillusson
- Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Inserm U1235 Nantes, Université de Nantes, 1 rue Gaston Veil, 44035, Nantes, France
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
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Lamontagne-Proulx J, Coulombe K, Dahhani F, Côté M, Guyaz C, Tremblay C, Di Marzo V, Flamand N, Calon F, Soulet D. Effect of Docosahexaenoic Acid (DHA) at the Enteric Level in a Synucleinopathy Mouse Model. Nutrients 2021; 13:nu13124218. [PMID: 34959768 PMCID: PMC8703327 DOI: 10.3390/nu13124218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/15/2022] Open
Abstract
The aggregation of alpha-synuclein protein (αSyn) is a hallmark of Parkinson’s disease (PD). Considerable evidence suggests that PD involves an early aggregation of αSyn in the enteric nervous system (ENS), spreading to the brain. While it has previously been reported that omega-3 polyunsaturated fatty acids (ω-3 PUFA) acts as neuroprotective agents in the brain in murine models of PD, their effect in the ENS remains undefined. Here, we studied the effect of dietary supplementation with docosahexaenoic acid (DHA, an ω-3 PUFA), on the ENS, with a particular focus on enteric dopaminergic (DAergic) neurons. Thy1-αSyn mice, which overexpress human αSyn, were fed ad libitum with a control diet, a low ω-3 PUFA diet or a diet supplemented with microencapsulated DHA and then compared with wild-type littermates. Our data indicate that Thy1-αSyn mice showed a lower density of enteric dopaminergic neurons compared with non-transgenic animals. This decrease was prevented by dietary DHA. Although we found that DHA reduced microgliosis in the striatum, we did not observe any evidence of peripheral inflammation. However, we showed that dietary intake of DHA promoted a build-up of ω-3 PUFA-derived endocannabinoid (eCB)-like mediators in plasma and an increase in glucagon-like peptide-1 (GLP-1) and the redox regulator, Nrf2 in the ENS. Taken together, our results suggest that DHA exerts neuroprotection of enteric DAergic neurons in the Thy1-αSyn mice, possibly through alterations in eCB-like mediators, GLP-1 and Nrf2.
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Affiliation(s)
- Jérôme Lamontagne-Proulx
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
| | - Katherine Coulombe
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
| | - Fadil Dahhani
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, QC G1V 4G5, Canada; (F.D.); (V.D.); (N.F.)
- Canada Excellence Research in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC G1V 4G5, Canada
| | - Mélissa Côté
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
| | - Cédric Guyaz
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
| | - Cyntia Tremblay
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
| | - Vincenzo Di Marzo
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, QC G1V 4G5, Canada; (F.D.); (V.D.); (N.F.)
- Canada Excellence Research in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC G1V 4G5, Canada
- Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF) et Centre NUTRISS, Université Laval, Québec, QC G1V 0A6, Canada
| | - Nicolas Flamand
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, QC G1V 4G5, Canada; (F.D.); (V.D.); (N.F.)
- Canada Excellence Research in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC G1V 4G5, Canada
- Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Frédéric Calon
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
- Laboratoire International Associé OptiNutriBrain, (NutriNeuro France-INAF Canada), Québec, QC G1V 0A6, Canada
| | - Denis Soulet
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF) et Centre NUTRISS, Université Laval, Québec, QC G1V 0A6, Canada
- Correspondence: ; Tel.: +1-418-654-2296
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Pellegrini C, D'Antongiovanni V, Ippolito C, Segnani C, Antonioli L, Fornai M, Bernardini N. From the intestinal mucosal barrier to the enteric neuromuscular compartment: an integrated overview on the morphological changes in Parkinson's disease. Eur J Histochem 2021; 65. [PMID: 34802221 PMCID: PMC8636839 DOI: 10.4081/ejh.2021.3278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 10/20/2021] [Indexed: 11/22/2022] Open
Abstract
Gastrointestinal dysfunctions represent the most common non-motor symptoms in Parkinson’s disease (PD). Of note, changes in gut microbiota, impairments of intestinal epithelial barrier (IEB), bowel inflammation and neuroplastic rearrangements of the enteric nervous system (ENS) could be involved in the pathophysiology of the intestinal disturbances in PD. In this context, although several review articles have pooled together evidence on the alterations of enteric bacteria-neuro-immune network in PD, a revision of the literature on the specific morphological changes occurring in the intestinal mucosal barrier, the ENS and enteric muscular layers in PD, is lacking. The present review provides a complete appraisal of the available knowledge on the morphological alterations of intestinal mucosal barrier, with particular focus on IEB, ENS and enteric muscular layers in PD. In particular, our intent was to critically discuss whether, based on evidence from translational studies and preclinical models, morphological changes in the intestinal barrier and enteric neuromuscular compartment contribute to the pathophysiology of intestinal dysfunctions occurring in PD.
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Affiliation(s)
- Carolina Pellegrini
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa.
| | - Vanessa D'Antongiovanni
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa.
| | - Chiara Ippolito
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa.
| | - Cristina Segnani
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa.
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa.
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa.
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, Unit of Histology; Interdepartmental Research Center "Nutraceuticals and Food for Health", University of Pisa.
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Pasquini J, Brooks DJ, Pavese N. The Cholinergic Brain in Parkinson's Disease. Mov Disord Clin Pract 2021; 8:1012-1026. [PMID: 34631936 DOI: 10.1002/mdc3.13319] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/07/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
The central cholinergic system includes the basal forebrain nuclei, mainly projecting to the cortex, the mesopontine tegmental nuclei, mainly projecting to the thalamus and subcortical structures, and other groups of projecting neurons and interneurons. This system regulates many functions of human behavior such as cognition, locomotion, and sleep. In Parkinson's disease (PD), disruption of central cholinergic transmission has been associated with cognitive decline, gait problems, freezing of gait (FOG), falls, REM sleep behavior disorder (RBD), neuropsychiatric manifestations, and olfactory dysfunction. Neuropathological and neuroimaging evidence suggests that basal forebrain pathology occurs simultaneously with nigrostriatal denervation, whereas pathology in the pontine nuclei may occur before the onset of motor symptoms. These studies have also detailed the clinical implications of cholinergic dysfunction in PD. Degeneration of basal forebrain nuclei and consequential cortical cholinergic denervation are associated with and may predict the subsequent development of cognitive decline and neuropsychiatric symptoms. Gait problems, FOG, and falls are associated with a complex dysfunction of both pontine and basal forebrain nuclei. Olfactory impairment is associated with cholinergic denervation of the limbic archicortex, specifically hippocampus and amygdala. Available evidence suggests that cholinergic dysfunction, alongside failure of the dopaminergic and other neurotransmitters systems, contributes to the generation of a specific set of clinical manifestations. Therefore, a "cholinergic phenotype" can be identified in people presenting with cognitive decline, falls, and RBD. In this review, we will summarize the organization of the central cholinergic system and the clinical correlates of cholinergic dysfunction in PD.
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Affiliation(s)
- Jacopo Pasquini
- Department of Pathophysiology and Transplantation University of Milan Milan Italy.,Clinical Ageing Research Unit Newcastle University Newcastle upon Tyne United Kingdom
| | - David J Brooks
- Positron Emission Tomography Centre Newcastle University Newcastle upon Tyne United Kingdom.,Department of Nuclear Medicine and PET Centre Aarhus University Hospital Aarhus Denmark
| | - Nicola Pavese
- Clinical Ageing Research Unit Newcastle University Newcastle upon Tyne United Kingdom.,Department of Nuclear Medicine and PET Centre Aarhus University Hospital Aarhus Denmark
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Sharabi Y, Vatine GD, Ashkenazi A. Parkinson's disease outside the brain: targeting the autonomic nervous system. Lancet Neurol 2021; 20:868-876. [PMID: 34536407 DOI: 10.1016/s1474-4422(21)00219-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 04/13/2021] [Accepted: 07/02/2021] [Indexed: 01/09/2023]
Abstract
Patients with Parkinson's disease present with signs and symptoms of dysregulation of the peripheral autonomic nervous system that can even precede motor deficits. This dysregulation might reflect early pathology and therefore could be targeted for the development of prodromal or diagnostic biomarkers. Only a few objective clinical tests assess disease progression and are used to evaluate the entire spectrum of autonomic dysregulation in patients with Parkinson's disease. However, results from epidemiological studies and findings from new animal models suggest that the dysfunctional autonomic nervous system is a probable route by which Parkinson's disease pathology can spread both to and from the CNS. The autonomic innervation of the gut, heart, and skin is affected by α-synuclein pathology in the early stages of the disease and might initiate α-synuclein spread via the autonomic connectome to the CNS. The development of easy-to-use and reliable clinical tests of autonomic nervous system function seems crucial for early diagnosis, and for developing strategies to stop or prevent neurodegeneration in Parkinson's disease.
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Affiliation(s)
- Yehonatan Sharabi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Hypertension Unit, Chaim Sheba Medical Center, Tel-HaShomer, Israel
| | - Gad D Vatine
- Department of Physiology and Cell Biology, Faculty of Health Sciences, The Regenerative Medicine and Stem Cell (RMSC) Research Center and The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, Israel.
| | - Avraham Ashkenazi
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
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Bindas AJ, Kulkarni S, Koppes RA, Koppes AN. Parkinson's disease and the gut: Models of an emerging relationship. Acta Biomater 2021; 132:325-344. [PMID: 33857691 DOI: 10.1016/j.actbio.2021.03.071] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 12/17/2022]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disease characterized by a progressive loss of fine motor function that impacts 1-2 out of 1,000 people. PD occurs predominately late in life and lacks a definitive biomarker for early detection. Recent cross-disciplinary progress has implicated the gut as a potential origin of PD pathogenesis. The gut-origin hypothesis has motivated research on gut PD pathology and transmission to the brain, especially during the prodromal stage (10-20 years before motor symptom onset). Early findings have revealed several possible triggers for Lewy pathology - the pathological hallmark of PD - in the gut, suggesting that microbiome and epithelial interactions may play a greater than appreciated role. But the mechanisms driving Lewy pathology and gut-brain transmission in PD remain unknown. Development of artificial α-Synuclein aggregates (α-Syn preformed fibrils) and animal disease models have recapitulated features of PD progression, enabling for the first time, controlled investigation of the gut-origin hypothesis. However, the role of specific cells in PD transmission, such as neurons, remains limited and requires in vitro models for controlled evaluation and perturbation. Human cell populations, three-dimensional organoids, and microfluidics as discovery platforms inch us closer to improving existing treatment for patients by providing platforms for discovery and screening. This review includes a discussion of PD pathology, conventional treatments, in vivo and in vitro models, and future directions. STATEMENT OF SIGNIFICANCE: Parkinson's Disease remains a common neurodegenerative disease with palliative versus causal treatments. Recently, the gut-origin hypothesis, where Parkinson's disease is thought to originate and spread from the gut to the brain, has gained traction as a field of investigation. However, despite the wealth of studies and innovative approaches to accelerate the field, there remains a need for in vitro tools to enable fundamental biological understanding of disease progression, and compound screening and efficacy. In this review, we present a historical perspective of Parkinson's Disease pathogenesis, detection, and conventional therapy, animal and human models investigating the gut-origin hypothesis, in vitro models to enable controlled discovery, and future outlooks for this blossoming field.
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Affiliation(s)
- Adam J Bindas
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., 313 Snell Engineering, Boston, MA 02115, USA.
| | - Subhash Kulkarni
- Division of Gastroenterology and Hepatology, Johns Hopkins University, 720 Rutland Avenue., Baltimore, MD 21205, USA.
| | - Ryan A Koppes
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., 313 Snell Engineering, Boston, MA 02115, USA.
| | - Abigail N Koppes
- Department of Chemical Engineering, Northeastern University, 360 Huntington Ave., 313 Snell Engineering, Boston, MA 02115, USA; Department of Biology, Northeastern University, 360 Huntington Ave., 313 Snell Engineering, Boston, MA 02115, USA.
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39
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Nakamori H, Noda K, Mitsui R, Hashitani H. Role of enteric dopaminergic neurons in regulating peristalsis of rat proximal colon. Neurogastroenterol Motil 2021; 33:e14127. [PMID: 33939231 DOI: 10.1111/nmo.14127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 02/11/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Constipation is commonly seen in patients with Parkinson's disease associated with a loss of dopaminergic neurons in both central and enteric nervous systems. However, the roles of enteric dopaminergic neurons in developing constipation remain to be elucidated. Here, we investigated the roles of enteric dopaminergic neurons in the generation of colonic peristalsis. METHODS Cannulated segments of rat proximal colon were situated in the organ bath, abluminally perfused with physiological salt solution and luminally perfused with 0.9% saline. Drugs were applied in the abluminal solution. Changes in diameter along the length of the colonic segment were captured by a video camera and transformed into spatio-temporal maps. Fluorescence immunohistochemistry was also carried out. KEY RESULTS Blockade of nitrergic neurotransmission prevented oro-aboral propagation of peristaltic waves and caused a colonic constriction without affecting ripples, non-propagating myogenic contractions. Blockade of cholinergic neurotransmission also prevented peristaltic waves but suppressed ripples with a colonic dilatation. Tetrodotoxin (0.6 μM) abolished peristaltic waves and increased ripples with a constriction. SCH 23390 (20 μM), a D1 -like dopamine receptor antagonist, slowed the peristaltic waves and caused a constriction, while GBR 12909 (1 μM), a dopamine reuptake inhibitor, diminished the peristaltic waves with a dilatation. Bath-applied dopamine (3 μM) abolished the peristaltic waves associated with a colonic dilation in an SCH 23390 (5 μM)-sensitive manner. D1 receptor immunoreactivity was co-localized to nitrergic and cholinergic neurons. CONCLUSIONS AND INFERENCES Dopaminergic neurons appear to facilitate nitrergic neurons via D1 -like receptors to stabilize asynchronous contractile activity resulting in the generation of colonic peristalsis.
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Affiliation(s)
- Hiroyuki Nakamori
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kenta Noda
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Retsu Mitsui
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hikaru Hashitani
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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40
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Abstract
Glia, the non-neuronal cells of the nervous system, were long considered secondary cells only necessary for supporting the functions of their more important neuronal neighbors. Work by many groups over the past two decades has completely overturned this notion, revealing the myriad and vital functions of glia in nervous system development, plasticity, and health. The largest population of glia outside the brain is in the enteric nervous system, a division of the autonomic nervous system that constitutes a key node of the gut-brain axis. Here, we review the latest in the understanding of these enteric glia in mammals with a focus on their putative roles in human health and disease.
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Affiliation(s)
- Harry J. Rosenberg
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Meenakshi Rao
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
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41
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The Baseline Structure of the Enteric Nervous System and Its Role in Parkinson's Disease. Life (Basel) 2021; 11:life11080732. [PMID: 34440476 PMCID: PMC8400095 DOI: 10.3390/life11080732] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/14/2021] [Accepted: 07/20/2021] [Indexed: 12/17/2022] Open
Abstract
The gastrointestinal (GI) tract is provided with a peculiar nervous network, known as the enteric nervous system (ENS), which is dedicated to the fine control of digestive functions. This forms a complex network, which includes several types of neurons, as well as glial cells. Despite extensive studies, a comprehensive classification of these neurons is still lacking. The complexity of ENS is magnified by a multiple control of the central nervous system, and bidirectional communication between various central nervous areas and the gut occurs. This lends substance to the complexity of the microbiota–gut–brain axis, which represents the network governing homeostasis through nervous, endocrine, immune, and metabolic pathways. The present manuscript is dedicated to identifying various neuronal cytotypes belonging to ENS in baseline conditions. The second part of the study provides evidence on how these very same neurons are altered during Parkinson’s disease. In fact, although being defined as a movement disorder, Parkinson’s disease features a number of degenerative alterations, which often anticipate motor symptoms. Among these, the GI tract is often involved, and for this reason, it is important to assess its normal and pathological structure. A deeper knowledge of the ENS is expected to improve the understanding of diagnosis and treatment of Parkinson’s disease.
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42
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Singh A, Dawson TM, Kulkarni S. Neurodegenerative disorders and gut-brain interactions. J Clin Invest 2021; 131:e143775. [PMID: 34196307 DOI: 10.1172/jci143775] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Neurodegenerative disorders (NDs) affect essential functions not only in the CNS, but also cause persistent gut dysfunctions, suggesting that they have an impact on both CNS and gut-innervating neurons. Although the CNS biology of NDs continues to be well studied, how gut-innervating neurons, including those that connect the gut to the brain, are affected by or involved in the etiology of these debilitating and progressive disorders has been understudied. Studies in recent years have shown how CNS and gut biology, aided by the gut-brain connecting neurons, modulate each other's functions. These studies underscore the importance of exploring the gut-innervating and gut-brain connecting neurons of the CNS and gut function in health, as well as the etiology and progression of dysfunction in NDs. In this Review, we discuss our current understanding of how the various gut-innervating neurons and gut physiology are involved in the etiology of NDs, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, to cause progressive CNS and persistent gut dysfunction.
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Affiliation(s)
- Alpana Singh
- Center for Neurogastroenterology, Division of Gastroenterology and Hepatology, Department of Medicine
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering.,Department of Neurology.,Solomon H. Snyder Department of Neuroscience, and.,Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, USA
| | - Subhash Kulkarni
- Center for Neurogastroenterology, Division of Gastroenterology and Hepatology, Department of Medicine
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43
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Soliman H, Coffin B, Gourcerol G. Gastroparesis in Parkinson Disease: Pathophysiology, and Clinical Management. Brain Sci 2021; 11:831. [PMID: 34201699 PMCID: PMC8301889 DOI: 10.3390/brainsci11070831] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/16/2021] [Accepted: 06/22/2021] [Indexed: 02/07/2023] Open
Abstract
Patients with Parkinson disease (PD) experience a range of non-motor symptoms, including gastrointestinal symptoms. These symptoms can be present in the prodromal phase of the disease. Recent advances in pathophysiology reveal that α-synuclein aggregates that form Lewy bodies and neurites, the hallmark of PD, are present in the enteric nervous system and may precede motor symptoms. Gastroparesis is one of the gastrointestinal involvements of PD and is characterized by delayed gastric emptying of solid food in the absence of mechanical obstruction. Gastroparesis has been reported in nearly 45% of PD. The cardinal symptoms include early satiety, postprandial fullness, nausea, and vomiting. The diagnosis requires an appropriate test to confirm delayed gastric emptying, such as gastric scintigraphy, or breath test. Gastroparesis can lead to malnutrition and impairment of quality of life. Moreover, it might interfere with the absorption of antiparkinsonian drugs. The treatment includes dietary modifications, and pharmacologic agents both to accelerate gastric emptying and relieve symptoms. Alternative treatments have been recently developed in the management of gastroparesis, and their use in patients with PD will be reported in this review.
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Affiliation(s)
- Heithem Soliman
- Centre de Recherche sur l’Inflammation, Université de Paris, Inserm UMRS 1149, 75018 Paris, France;
- Département d’Hépato Gastro Entérologie, Hôpital Louis Mourier, DMU ESPRIT—GHU (AP-HP), 92700 Colombes, France
| | - Benoit Coffin
- Centre de Recherche sur l’Inflammation, Université de Paris, Inserm UMRS 1149, 75018 Paris, France;
- Département d’Hépato Gastro Entérologie, Hôpital Louis Mourier, DMU ESPRIT—GHU (AP-HP), 92700 Colombes, France
| | - Guillaume Gourcerol
- Centre Hospitalo-Universitaire de Rouen, INSERM UMR 1073, CIC-CRB 1404, 76000 Rouen, France;
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Beach TG, Adler CH, Sue LI, Shill HA, Driver-Dunckley E, Mehta SH, Intorcia AJ, Glass MJ, Walker JE, Arce R, Nelson CM, Serrano GE. Vagus Nerve and Stomach Synucleinopathy in Parkinson's Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the "Body-First" Hypothesis. JOURNAL OF PARKINSONS DISEASE 2021; 11:1833-1843. [PMID: 34151862 PMCID: PMC10082635 DOI: 10.3233/jpd-212733] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson's disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. OBJECTIVE We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. METHODS Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. RESULTS Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. CONCLUSION As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease.
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Affiliation(s)
| | - Charles H Adler
- Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Lucia I Sue
- Banner Sun Health Research Institute, Sun City, AZ, USA
| | | | | | - Shyamal H Mehta
- Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | | | | | | | - Richard Arce
- Banner Sun Health Research Institute, Sun City, AZ, USA
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Schaffernicht G, Shang Q, Stievenard A, Bötzel K, Dening Y, Kempe R, Toussaint M, Gündel D, Kranz M, Reichmann H, Vanbesien-Mailliot C, Brust P, Dieterich M, Funk RHW, Ravens U, Pan-Montojo F. Pathophysiological Changes in the Enteric Nervous System of Rotenone-Exposed Mice as Early Radiological Markers for Parkinson's Disease. Front Neurol 2021; 12:642604. [PMID: 33841309 PMCID: PMC8030242 DOI: 10.3389/fneur.2021.642604] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/25/2021] [Indexed: 12/02/2022] Open
Abstract
Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.
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Affiliation(s)
- Gabriela Schaffernicht
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
| | - Qi Shang
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
| | - Alicia Stievenard
- Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France
| | - Kai Bötzel
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Yanina Dening
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
| | - Romy Kempe
- Department of Pharmacology and Toxicology, TU-Dresden, Dresden, Germany
| | - Magali Toussaint
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany
| | - Daniel Gündel
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany
| | - Mathias Kranz
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany
| | - Heinz Reichmann
- Department of Neurology, Technische Universität Dresden, Dresden, Germany.,Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Christel Vanbesien-Mailliot
- Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France
| | - Peter Brust
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany
| | - Marianne Dieterich
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.,German Center for Vertigo and Balance Disorders, University Hospital, LMU Munich, Munich, Germany
| | - Richard H W Funk
- Center for Regenerative Therapies Dresden, Dresden, Germany.,Institute for Anatomy, Technical University (TU)-Dresden, Dresden, Germany
| | - Ursula Ravens
- Department of Pharmacology and Toxicology, TU-Dresden, Dresden, Germany.,Institute for Experimental Cardiovascular Medicine, University Heart Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Francisco Pan-Montojo
- Department of Neurology, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.,Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
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46
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Gastrointestinal Dysfunction in Parkinson's Disease. J Clin Med 2021; 10:jcm10030493. [PMID: 33572547 PMCID: PMC7866791 DOI: 10.3390/jcm10030493] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/24/2021] [Accepted: 01/26/2021] [Indexed: 12/19/2022] Open
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease. Patients show deposits of pathological, aggregated α-synuclein not only in the brain but throughout almost the entire length of the digestive tract. This gives rise to non-motor symptoms particularly within the gastrointestinal tract and patients experience a wide range of frequent and burdensome symptoms such as dysphagia, bloating, and constipation. Recent evidence suggests that progressive accumulation of gastrointestinal pathology is underway several years before a clinical diagnosis of PD. Notably, constipation has been shown to increase the risk of developing PD and in contrast, truncal vagotomy seems to decrease the risk of PD. Animal models have demonstrated gut-to-brain spreading of pathological α-synuclein and it is currently being intensely studied whether PD begins in the gut of some patients. Gastrointestinal symptoms in PD have been investigated by the use of several different questionnaires. However, there is limited correspondence between subjective gastrointestinal symptoms and objective dysfunction along the gastrointestinal tract, and often the magnitude of dysfunction is underestimated by the use of questionnaires. Therefore, objective measures are important tools to clarify the degree of dysfunction in future studies of PD. Here, we summarize the types and prevalence of subjective gastrointestinal symptoms and objective dysfunction in PD. The potential importance of the gastrointestinal tract in the etiopathogenesis of PD is briefly discussed.
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47
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Tanei ZI, Saito Y, Ito S, Matsubara T, Motoda A, Yamazaki M, Sakashita Y, Kawakami I, Ikemura M, Tanaka S, Sengoku R, Arai T, Murayama S. Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases. Acta Neuropathol 2021; 141:25-37. [PMID: 33150517 PMCID: PMC7785549 DOI: 10.1007/s00401-020-02233-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 01/05/2023]
Abstract
Lewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson's disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptoms. To clarify the role of ENS Lewy pathology in disease progression, we performed a clinicopathological study using the Brain Bank for Aging Research in Japan. Five-hundred and eighteen cases were enrolled in the study. Lewy pathology of the CNS and PNS, including the lower esophagus as a representative of the ENS, was examined via autopsy findings. Results showed that one-third of older people (178 cases, 34%) exhibited Lewy pathology, of which 78 cases (43.8%) exhibited the pathology in the esophagus. In the esophageal wall, Auerbach's plexus (41.6%) was most susceptible to the pathology, followed by the adventitia (33.1%) and Meissner's plexus (14.6%). Lewy pathology of the esophagus was significantly associated with autonomic failures such as constipation (p < 0.0001) and among PNS regions, correlated the most with LBD progression (r = 0.95, p < 0.05). These findings suggest that the propagation of esophageal Lewy pathology is a predictive factor of LBD.
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Affiliation(s)
- Zen-Ichi Tanei
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Yuko Saito
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
| | - Shinji Ito
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
| | - Tomoyasu Matsubara
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Atsuko Motoda
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Mikihiro Yamazaki
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yasuhiro Sakashita
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Ito Kawakami
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Masako Ikemura
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shinya Tanaka
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
- Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo, Japan
| | - Renpei Sengoku
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan
- Department of Neurology, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
| | - Shigeo Murayama
- Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
- Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, United Graduate School of Child Development, Osaka University, Osaka, Japan.
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48
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Cossais F, Schaeffer E, Heinzel S, Zimmermann J, Niesler B, Röth R, Rappold G, Scharf A, Zorenkov D, Lange C, Barrenschee M, Margraf NG, Ellrichmann M, Berg D, Böttner M, Wedel T. Expression Profiling of Rectal Biopsies Suggests Altered Enteric Neuropathological Traits in Parkinson's Disease Patients. JOURNAL OF PARKINSONS DISEASE 2020; 11:171-176. [PMID: 33337386 DOI: 10.3233/jpd-202258] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Still little is known about the nature of the gastrointestinal pathological alterations occurring in Parkinson's disease (PD). Here, we used multiplexed mRNA profiling to measure the expression of a panel of 770 genes related to neuropathological processes in deep submucosal rectal biopsies of PD patients and healthy controls. Altered enteric neuropathological traits based on the expression of 22 genes related to neuroglial and mitochondrial functions, vesicle trafficking and inflammation was observed in 9 out of 12 PD patients in comparison to healthy controls. These results provide new evidences that intestinal neuropathological alterations may occur in a large proportion of PD patients.
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Affiliation(s)
- François Cossais
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Eva Schaeffer
- Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Sebastian Heinzel
- Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Jessica Zimmermann
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Beate Niesler
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.,nCounter Core Facility, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.,Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
| | - Ralph Röth
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.,nCounter Core Facility, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Gudrun Rappold
- Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.,nCounter Core Facility, Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany.,Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
| | - Amelie Scharf
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Dmitri Zorenkov
- Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Christina Lange
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | | | - Nils G Margraf
- Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Mark Ellrichmann
- Interdisciplinary Endoscopy, Medical Department I, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Daniela Berg
- Department of Neurology, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Martina Böttner
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Thilo Wedel
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
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49
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Bu LL, Huang KX, Zheng DZ, Lin DY, Chen Y, Jing XN, Liang YR, Tao EX. Alpha-Synuclein Accumulation and Its Phosphorylation in the Enteric Nervous System of Patients Without Neurodegeneration: An Explorative Study. Front Aging Neurosci 2020; 12:575481. [PMID: 33328957 PMCID: PMC7719782 DOI: 10.3389/fnagi.2020.575481] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 10/09/2020] [Indexed: 12/17/2022] Open
Abstract
Alpha-synuclein (α-Syn) is widely distributed and involved in the regulation of the nervous system. The phosphorylation of α-Syn at serine 129 (pSer129α-Syn) is known to be closely associated with α-Synucleinopathies, especially Parkinson's disease (PD). The present study aimed to explore the α-Syn accumulation and its phosphorylation in the enteric nervous system (ENS) in patients without neurodegeneration. Patients who underwent colorectal surgery for either malignant or benign tumors that were not suitable for endoscopic resection (n = 19) were recruited to obtain normal intestinal specimens, which were used to assess α-Syn immunoreactivity patterns using α-Syn and pSer129α-Syn antibodies. Furthermore, the sub-location of α-Syn in neurons was identified by α-Syn/neurofilament double staining. Semi-quantitative counting was used to evaluate the expression of α-Syn and pSer129α-Syn in the ENS. Positive staining of α-Syn was detected in all intestinal layers in patients with non-neurodegenerative diseases. There was no significant correlation between the distribution of α-Syn and age (p = 0.554) or tumor stage (p = 0.751). Positive staining for pSer129α-Syn was only observed in the submucosa and myenteric plexus layers. The accumulation of pSer129α-Syn increased with age. In addition, we found that the degenerative changes of the ENS were related to the degree of tumor malignancy (p = 0.022). The deposits of α-Syn were present in the ENS of patients with non-neurodegenerative disorders; particularly the age-dependent expression of pSer129α-Syn in the submucosa and myenteric plexus. The current findings of α-Syn immunostaining in the ENS under near non-pathological conditions weaken the basis of using α-Syn pathology as a suitable hallmark to diagnose α-Synucleinopathies including PD. However, our data provided unique perspectives to study gastrointestinal dysfunction in non-neurodegenerative disorders. These findings provide new evidence to elucidate the neuropathological characteristics and α-Syn pathology pattern of the ENS in non-neurodegenerative conditions.
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Affiliation(s)
- Lu-Lu Bu
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kai-Xun Huang
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - De-Zhi Zheng
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dan-Yu Lin
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Ying Chen
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiu-Na Jing
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan-Ran Liang
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - En-Xiang Tao
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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Lamotte G, Holmes C, Sullivan P, Lenka A, Goldstein DS. Cardioselective peripheral noradrenergic deficiency in Lewy body synucleinopathies. Ann Clin Transl Neurol 2020; 7:2450-2460. [PMID: 33216462 PMCID: PMC7732242 DOI: 10.1002/acn3.51243] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 10/20/2020] [Indexed: 12/18/2022] Open
Abstract
Objective Lewy body (LB) synucleinopathies such as Parkinson’s disease (PD) entail profound cardiac norepinephrine deficiency. The status of sympathetic noradrenergic innervation at other extracranial sites has been unclear. Although in vivo neuroimaging studies have indicated a cardioselective noradrenergic lesion, no previous study has surveyed peripheral organs for norepinephrine contents in LB diseases. We reviewed 18F‐dopamine (18F‐DA) positron emission tomographic images and postmortem neurochemical data across several body organs of controls and patients with the LB synucleinopathies PD and pure autonomic failure (PAF) and the non‐LB synucleinopathy multiple system atrophy (MSA). Methods 18F‐DA–derived radioactivity in the heart, liver, spleen, pancreas, stomach, kidneys, thyroid, and submandibular glands were analyzed from 145 patients with LB synucleinopathies (112 PD, 33 PAF), 74 controls, and 85 MSA patients. In largely separate cohorts, postmortem tissue norepinephrine data were reviewed for heart, liver, spleen, pancreas, kidney, thyroid, submandibular gland, and sympathetic ganglion tissue from 38 PD, 2 PAF, and 5 MSA patients and 35 controls. Results Interventricular septal 18F‐DA–derived radioactivity was decreased in the LB synucleinopathy group compared to the control and MSA groups (P < 0.0001 each). The LB and non‐LB groups did not differ in liver, spleen, pancreas, stomach, or kidney 18F‐DA–derived radioactivity. The LB synucleinopathy group had markedly decreased apical myocardial norepinephrine, but normal tissue norepinephrine in other organs. The MSA group had normal tissue norepinephrine in all examined organs. Interpretation By in vivo sympathetic neuroimaging and postmortem neurochemistry peripheral noradrenergic deficiency in LB synucleinopathies is cardioselective. MSA does not involve peripheral noradrenergic deficiency.
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Affiliation(s)
- Guillaume Lamotte
- Clinical Neurosciences Program (CNP), Division of Intramural Research (DIR), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA.,Autonomic Medicine Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA
| | - Courtney Holmes
- Autonomic Medicine Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA
| | - Patricia Sullivan
- Autonomic Medicine Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA
| | - Abhishek Lenka
- Department of Neurology, Medstar Georgetown University Hospital, Washington, District of Columbia, USA
| | - David S Goldstein
- Autonomic Medicine Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA
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