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Simmons DA, Selvaraj S, Chen T, Cao G, Camelo TS, McHugh TL, Gonzalez S, Martin RM, Simanauskaite J, Uchida N, Porteus MH, Longo FM. Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington's disease phenotypes. Mol Ther Methods Clin Dev 2025; 33:101415. [PMID: 39995448 PMCID: PMC11848452 DOI: 10.1016/j.omtm.2025.101415] [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] [Received: 11/13/2024] [Accepted: 01/20/2025] [Indexed: 02/26/2025]
Abstract
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSCs) offer a scalable platform for NT delivery but have potential safety risks including teratoma formation. We engineered hPSCs to constitutively produce BDNF and contain inducible safeguards to eliminate these cells if safety concerns arise. This study examined the efficacy of intrastriatally transplanted striatal progenitor cells (STRpcs) derived from these hPSCs against HD phenotypes in R6/2 mice. Engrafted STRpcs overexpressing BDNF alleviated motor and cognitive deficits and reduced mutant huntingtin aggregates. Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic.
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Affiliation(s)
- Danielle A. Simmons
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Sridhar Selvaraj
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tingshuo Chen
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Gloria Cao
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Talita Souto Camelo
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Tyne L.M. McHugh
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Selena Gonzalez
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Renata M. Martin
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Juste Simanauskaite
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Nobuko Uchida
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Matthew H. Porteus
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Frank M. Longo
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA
- Wu Tsai Neuroscience Institute, Stanford University, Stanford, CA 94305, USA
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Chen H, Li J, Huang Z, Fan X, Wang X, Chen X, Guo H, Liu H, Li S, Yu S, Li H, Huang X, Ma X, Deng X, Wang C, Liu Y. Dopaminergic system and neurons: Role in multiple neurological diseases. Neuropharmacology 2024; 260:110133. [PMID: 39197818 DOI: 10.1016/j.neuropharm.2024.110133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/24/2024] [Accepted: 08/25/2024] [Indexed: 09/01/2024]
Abstract
The dopaminergic system is a complex and powerful neurotransmitter system in the brain. It plays an important regulatory role in motivation, reward, cognition, and motor control. In recent decades, research in the field of the dopaminergic system and neurons has increased exponentially and is gradually becoming a point of intervention in the study and understanding of a wide range of neurological diseases related to human health. Studies have shown that the dopaminergic system and neurons are involved in the development of many neurological diseases (including, but not limited to Parkinson's disease, schizophrenia, depression, attention deficit hyperactivity disorder, etc.) and that dopaminergic neurons either have too much stress or too weak function in the dopaminergic system can lead to disease. Therefore, targeting dopaminergic neurons is considered key to treating these diseases. This article provides a comprehensive review of the dopaminergic system and neurons in terms of brain region distribution, physiological function and subtypes of dopaminergic neurons, as well as the role of the dopaminergic system and neurons in a variety of diseases.
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Affiliation(s)
- Heng Chen
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Jieshu Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Zhixing Huang
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaoxiao Fan
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xiaofei Wang
- Beijing Normal University, Beijing, 100875, China
| | - Xing Chen
- University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Haitao Guo
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Hao Liu
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shuqi Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shaojun Yu
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Honghong Li
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xinyu Huang
- Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xuehua Ma
- Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Xinqi Deng
- Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Chunguo Wang
- Beijing University of Chinese Medicine, Beijing, 102488, China.
| | - Yonggang Liu
- Beijing University of Chinese Medicine, Beijing, 102488, China.
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Salem S, Alpaugh M, Saint-Pierre M, Alves-Martins-Borba FN, Cerquera-Cleves C, Lemieux M, Ngonza-Nito SB, De Koninck P, Melki R, Cicchetti F. Treatment with Tau fibrils impact Huntington's disease-related phenotypes in cell and mouse models. Neurobiol Dis 2024; 202:106696. [PMID: 39389154 DOI: 10.1016/j.nbd.2024.106696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/13/2024] [Accepted: 10/04/2024] [Indexed: 10/12/2024] Open
Abstract
There is now compelling evidence for the presence of pathological forms of Tau in tissues of both patients and animal models of Huntington's disease (HD). While the root cause of this illness is a mutation within the huntingtin gene, a number of studies now suggest that HD could also be considered a secondary tauopathy. However, the contributory role of Tau in the pathogenesis and pathophysiology of this condition, as well as its implications in cellular toxicity and consequent behavioral impairments are largely unknown. We therefore performed intracerebral stereotaxic injections of recombinant human Tau monomers and fibrils into the knock-in zQ175 mouse model of HD. Tau fibrils induced cognitive and anxiety-like phenotypes predominantly in zQ175 mice and increased the number and size of insoluble mutant huntingtin (mHTT) aggregates in the brains of treated animals. To better understand the putative mechanisms through which Tau could initiate and/or contribute to pathology, we incubated StHdh striatal cells, an in vitro model of HD, with the different Tau forms and evaluated the effects on cell functionality and heat shock proteins Hsp70 and Hsp90. Calcium imaging experiments showed functional impairments of HD StHdh cells following treatment with Tau fibrils, as well as significant changes to the levels of both heat shock proteins which were found trapped within mHTT aggregates. The accumulation of Hsp70 and 90 within aggregates was also present in mouse tissue which suggests that alteration of molecular chaperone-dependent protein quality control may influence aggregation, implicating proteostasis in the mHTT-Tau interplay.
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Affiliation(s)
- Shireen Salem
- Cente de Recherche du CHU de Québec, Axe Neurosciences, T2-07, 2705, Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de Médecine Moléculaire, Université Laval, Québec, QC, Canada
| | - Melanie Alpaugh
- Cente de Recherche du CHU de Québec, Axe Neurosciences, T2-07, 2705, Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de Psychiatrie et Neurosciences, Université Laval, Québec, QC, Canada
| | - Martine Saint-Pierre
- Cente de Recherche du CHU de Québec, Axe Neurosciences, T2-07, 2705, Boulevard Laurier, Québec, QC G1V 4G2, Canada
| | - Flavia Natale Alves-Martins-Borba
- Cente de Recherche du CHU de Québec, Axe Neurosciences, T2-07, 2705, Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de Psychiatrie et Neurosciences, Université Laval, Québec, QC, Canada
| | - Catalina Cerquera-Cleves
- Cente de Recherche du CHU de Québec, Axe Neurosciences, T2-07, 2705, Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de Psychiatrie et Neurosciences, Université Laval, Québec, QC, Canada
| | - Mado Lemieux
- CERVO Brain Research Center, 2601 de la Canardière, Québec, QC G1J 2G3, Canada
| | - Soki Bradel Ngonza-Nito
- Labortory of Neurodegenerative Diseases, Institut François Jacob, MIRCen, CEA, CNRS, Fontenay-aux-Roses, France
| | - Paul De Koninck
- CERVO Brain Research Center, 2601 de la Canardière, Québec, QC G1J 2G3, Canada
| | - Ronald Melki
- Labortory of Neurodegenerative Diseases, Institut François Jacob, MIRCen, CEA, CNRS, Fontenay-aux-Roses, France
| | - Francesca Cicchetti
- Cente de Recherche du CHU de Québec, Axe Neurosciences, T2-07, 2705, Boulevard Laurier, Québec, QC G1V 4G2, Canada; Département de Médecine Moléculaire, Université Laval, Québec, QC, Canada; Département de Psychiatrie et Neurosciences, Université Laval, Québec, QC, Canada.
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Nateghi B, Keraudren R, Boulay G, Bazin M, Goupil C, Canet G, Loiselle A, St-Amour I, Planel E, Soulet D, Hébert SS. Beneficial effects of miR-132/212 deficiency in the zQ175 mouse model of Huntington's disease. Front Neurosci 2024; 18:1421680. [PMID: 39170678 PMCID: PMC11337869 DOI: 10.3389/fnins.2024.1421680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/10/2024] [Indexed: 08/23/2024] Open
Abstract
Huntington's disease (HD) is a rare genetic neurodegenerative disorder caused by an expansion of CAG repeats in the Huntingtin (HTT) gene. One hypothesis suggests that the mutant HTT gene contributes to HD neuropathology through transcriptional dysregulation involving microRNAs (miRNAs). In particular, the miR-132/212 cluster is strongly diminished in the HD brain. This study explores the effects of miR-132/212 deficiency specifically in adult HD zQ175 mice. The absence of miR-132/212 did not impact body weight, body temperature, or survival rates. Surprisingly, miR-132/212 loss seemed to alleviate, in part, the effects on endogenous Htt expression, HTT inclusions, and neuronal integrity in HD zQ175 mice. Additionally, miR-132/212 depletion led to age-dependent improvements in certain motor functions. Transcriptomic analysis revealed alterations in HD-related networks in WT- and HD zQ175-miR-132/212-deficient mice, including significant overlap in BDNF and Creb1 signaling pathways. Interestingly, however, a higher number of miR-132/212 gene targets was observed in HD zQ175 mice lacking the miR-132/212 cluster, especially in the striatum. These findings suggest a nuanced interplay between miR-132/212 expression and HD pathogenesis, providing potential insights into therapeutic interventions. Further investigation is needed to fully understand the underlying mechanisms and therapeutic potential of modulating miR-132/212 expression during HD progression.
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Affiliation(s)
- Behnaz Nateghi
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
- Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, QC, Canada
| | - Remi Keraudren
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
- Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, QC, Canada
| | - Gabriel Boulay
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
- Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, QC, Canada
| | - Marc Bazin
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
| | - Claudia Goupil
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
| | - Geoffrey Canet
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
| | - Andréanne Loiselle
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
| | - Isabelle St-Amour
- CERVO Brain Research Centre, Centre Intégré Universitaire de Santé et des Services Sociaux de la Capitale-Nationale, Québec, QC, Canada
| | - Emmanuel Planel
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
- Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, QC, Canada
| | - Denis Soulet
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| | - Sébastien S. Hébert
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, CHUL, Québec, QC, Canada
- Département de Psychiatrie et de Neurosciences, Faculté de Médecine, Université Laval, Québec, QC, Canada
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Baj J, Flieger W, Barbachowska A, Kowalska B, Flieger M, Forma A, Teresiński G, Portincasa P, Buszewicz G, Radzikowska-Büchner E, Flieger J. Consequences of Disturbing Manganese Homeostasis. Int J Mol Sci 2023; 24:14959. [PMID: 37834407 PMCID: PMC10573482 DOI: 10.3390/ijms241914959] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/01/2023] [Accepted: 10/04/2023] [Indexed: 10/15/2023] Open
Abstract
Manganese (Mn) is an essential trace element with unique functions in the body; it acts as a cofactor for many enzymes involved in energy metabolism, the endogenous antioxidant enzyme systems, neurotransmitter production, and the regulation of reproductive hormones. However, overexposure to Mn is toxic, particularly to the central nervous system (CNS) due to it causing the progressive destruction of nerve cells. Exposure to manganese is widespread and occurs by inhalation, ingestion, or dermal contact. Associations have been observed between Mn accumulation and neurodegenerative diseases such as manganism, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. People with genetic diseases associated with a mutation in the gene associated with impaired Mn excretion, kidney disease, iron deficiency, or a vegetarian diet are at particular risk of excessive exposure to Mn. This review has collected data on the current knowledge of the source of Mn exposure, the experimental data supporting the dispersive accumulation of Mn in the brain, the controversies surrounding the reference values of biomarkers related to Mn status in different matrices, and the competitiveness of Mn with other metals, such as iron (Fe), magnesium (Mg), zinc (Zn), copper (Cu), lead (Pb), calcium (Ca). The disturbed homeostasis of Mn in the body has been connected with susceptibility to neurodegenerative diseases, fertility, and infectious diseases. The current evidence on the involvement of Mn in metabolic diseases, such as type 2 diabetes mellitus/insulin resistance, osteoporosis, obesity, atherosclerosis, and non-alcoholic fatty liver disease, was collected and discussed.
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Affiliation(s)
- Jacek Baj
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (W.F.); (A.F.)
| | - Wojciech Flieger
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (W.F.); (A.F.)
| | - Aleksandra Barbachowska
- Department of Plastic, Reconstructive and Burn Surgery, Medical University of Lublin, 21-010 Łęczna, Poland;
| | - Beata Kowalska
- Department of Water Supply and Wastewater Disposal, Lublin University of Technology, 20-618 Lublin, Poland;
| | - Michał Flieger
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.F.); (G.T.); (G.B.)
| | - Alicja Forma
- Chair and Department of Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; (W.F.); (A.F.)
| | - Grzegorz Teresiński
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.F.); (G.T.); (G.B.)
| | - Piero Portincasa
- Clinica Medica A. Murri, Department of Biomedical Sciences & Human Oncology, Medical School, University of Bari, 70124 Bari, Italy;
| | - Grzegorz Buszewicz
- Chair and Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; (M.F.); (G.T.); (G.B.)
| | | | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland
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Jiang A, Handley RR, Lehnert K, Snell RG. From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington's Disease Research. Int J Mol Sci 2023; 24:13021. [PMID: 37629202 PMCID: PMC10455900 DOI: 10.3390/ijms241613021] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
Huntington's disease (HD) is a debilitating neurodegenerative genetic disorder caused by an expanded polyglutamine-coding (CAG) trinucleotide repeat in the huntingtin (HTT) gene. HD behaves as a highly penetrant dominant disorder likely acting through a toxic gain of function by the mutant huntingtin protein. Widespread cellular degeneration of the medium spiny neurons of the caudate nucleus and putamen are responsible for the onset of symptomology that encompasses motor, cognitive, and behavioural abnormalities. Over the past 150 years of HD research since George Huntington published his description, a plethora of pathogenic mechanisms have been proposed with key themes including excitotoxicity, dopaminergic imbalance, mitochondrial dysfunction, metabolic defects, disruption of proteostasis, transcriptional dysregulation, and neuroinflammation. Despite the identification and characterisation of the causative gene and mutation and significant advances in our understanding of the cellular pathology in recent years, a disease-modifying intervention has not yet been clinically approved. This review includes an overview of Huntington's disease, from its genetic aetiology to clinical presentation and its pathogenic manifestation. An updated view of molecular mechanisms and the latest therapeutic developments will also be discussed.
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Affiliation(s)
- Andrew Jiang
- Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand; (R.R.H.); (K.L.); (R.G.S.)
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Speidell A, Bin Abid N, Yano H. Brain-Derived Neurotrophic Factor Dysregulation as an Essential Pathological Feature in Huntington's Disease: Mechanisms and Potential Therapeutics. Biomedicines 2023; 11:2275. [PMID: 37626771 PMCID: PMC10452871 DOI: 10.3390/biomedicines11082275] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is a major neurotrophin whose loss or interruption is well established to have numerous intersections with the pathogenesis of progressive neurological disorders. There is perhaps no greater example of disease pathogenesis resulting from the dysregulation of BDNF signaling than Huntington's disease (HD)-an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive impairments associated with basal ganglia dysfunction and the ultimate death of striatal projection neurons. Investigation of the collection of mechanisms leading to BDNF loss in HD highlights this neurotrophin's importance to neuronal viability and calls attention to opportunities for therapeutic interventions. Using electronic database searches of existing and forthcoming research, we constructed a literature review with the overarching goal of exploring the diverse set of molecular events that trigger BDNF dysregulation within HD. We highlighted research that investigated these major mechanisms in preclinical models of HD and connected these studies to those evaluating similar endpoints in human HD subjects. We also included a special focus on the growing body of literature detailing key transcriptomic and epigenetic alterations that affect BDNF abundance in HD. Finally, we offer critical evaluation of proposed neurotrophin-directed therapies and assessed clinical trials seeking to correct BDNF expression in HD individuals.
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Affiliation(s)
- Andrew Speidell
- Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; (A.S.); (N.B.A.)
| | - Noman Bin Abid
- Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; (A.S.); (N.B.A.)
| | - Hiroko Yano
- Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; (A.S.); (N.B.A.)
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
- Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
- Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
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Ehinger Y, Soneja D, Phamluong K, Salvi A, Ron D. Identification of Novel BDNF-Specific Corticostriatal Circuitries. eNeuro 2023; 10:ENEURO.0238-21.2023. [PMID: 37156610 PMCID: PMC10198608 DOI: 10.1523/eneuro.0238-21.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 03/23/2023] [Accepted: 04/03/2023] [Indexed: 05/10/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is released from axon terminals originating in the cerebral cortex onto striatal neurons. Here, we characterized BDNF neurons in the corticostriatal circuitry. First, we used BDNF-Cre and Ribotag transgenic mouse lines to label BDNF-positive neurons in the cortex and detected BDNF expression in all the subregions of the prefrontal cortex (PFC). Next, we used a retrograde viral tracing strategy, in combination with BDNF-Cre knock-in mice, to map the cortical outputs of BDNF neurons in the dorsomedial and dorsolateral striatum (DMS and DLS, respectively). We found that BDNF-expressing neurons located in the medial prefrontal cortex (mPFC) project mainly to the DMS, and those located in the primary and secondary motor cortices (M1 and M2, respectively) and agranular insular cortex (AI) project mainly to the DLS. In contrast, BDNF-expressing orbitofrontal cortical (OFC) neurons differentially target the dorsal striatum (DS) depending on their mediolateral and rostrocaudal location. Specifically, the DMS is mainly innervated by the medial and ventral part of the orbitofrontal cortex (MO and VO, respectively), whereas the DLS receives projections specifically from the lateral part of the OFC (LO). Together, our study uncovers previously unknown BDNF corticostriatal circuitries. These findings could have important implications for the role of BDNF signaling in corticostriatal pathways.
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Affiliation(s)
- Yann Ehinger
- Department of Neurology, University of California, San Francisco, 94143-0663 CA
| | - Drishti Soneja
- Department of Neurology, University of California, San Francisco, 94143-0663 CA
| | - Khanhky Phamluong
- Department of Neurology, University of California, San Francisco, 94143-0663 CA
| | - Alexandra Salvi
- Department of Neurology, University of California, San Francisco, 94143-0663 CA
| | - Dorit Ron
- Department of Neurology, University of California, San Francisco, 94143-0663 CA
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Han JY, Seo J, Choi Y, Im W, Ban JJ, Sung JJ. CRISPR-Cas9 mediated genome editing of Huntington's disease neurospheres. Mol Biol Rep 2023; 50:2127-2136. [PMID: 36550260 DOI: 10.1007/s11033-022-08175-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Huntington's disease (HD) is a fatal genetic disease caused by polyglutamine aggregation encoded by an expanded CAG repeat in the huntingtin gene (HTT). In this study, we cultured neurospheres derived from R6/2 mice, a representative animal model of HD, as an in vitro model. GuideRNAs were designed to induce large deletion or frameshift indel mutation of CAG expansion. These gRNAs and Cas9 were delivered to the R6/2 neurospheres and disease-related phenotypes were observed. METHODS AND RESULTS Deletion or indel mutation of the CAG repeat was confirmed by PCR, T7E1 assay and sequencing of the edited neurospheres. Edited neurospheres showed decreased polyglutamine aggregation compared with control HD neurospheres. In the edited neurosphere, we confirmed the upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and brain-derived neurotrophic factor (BDNF), whose reduced expressions are closely involved in the disease progression. In addition, flow cytometry result showed an increase in cell viability with an overall decrease in necrotic and apoptotic populations among edited R6/2 neurospheres. Additional siRNA experiments confirmed that the increased viability was decreased through inhibition of PGC-1α or BDNF. CONCLUSION Our study confirmed that CAG repeat of R6/2 mouse-derived neurospheres can be edited through CRISPR-Cas9. Editing of CAG repeat sequence decreases polyglutamine aggregation and cellular apoptosis of HD neurospheres, which may be related to the increased expressions of PGC-1α and BDNF. Our data provide the evidence that CRISPR-Cas9 mediated genome editing has therapeutic potential on HD neuronal cells.
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Affiliation(s)
- Ji Yun Han
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Jaewoo Seo
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea
| | - Yoori Choi
- Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.,Department of Nuclear Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Wooseok Im
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.,Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae-Jun Ban
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea. .,Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
| | - Jung-Joon Sung
- Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea. .,Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea. .,Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
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Maloney MT, Wang W, Bhowmick S, Millan I, Kapur M, Herrera N, Frost E, Zhang EY, Song S, Wang M, Park AB, Yao AY, Yang Y. Failure to Thrive: Impaired BDNF Transport along the Cortical-Striatal Axis in Mouse Q140 Neurons of Huntington's Disease. BIOLOGY 2023; 12:biology12020157. [PMID: 36829435 PMCID: PMC9952218 DOI: 10.3390/biology12020157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 01/20/2023]
Abstract
Boosting trophic support to striatal neurons by increasing levels of brain-derived neurotrophic factor (BDNF) has been considered as a target for therapeutic intervention for several neurodegenerative diseases, including Huntington's disease (HD). To aid in the implementation of such a strategy, a thorough understanding of BDNF cortical-striatal transport is critical to help guide its strategic delivery. In this manuscript, we investigate the dynamic behavior of BDNF transport along the cortical-striatal axis in Q140 primary neurons, a mouse model for HD. We examine this by using single-molecule labeling of BDNF conjugated with quantum dots (QD-BDNF) to follow the transport along the cortical-striatal axis in a microfluidic chamber system specifically designed for the co-culture of cortical and striatal primary neurons. Using this approach, we observe a defect of QD-BDNF transport in Q140 neurons. Our study demonstrates that QD-BDNF transport along the cortical-striatal axis involves the impairment of anterograde transport within axons of cortical neurons, and of retrograde transport within dendrites of striatal neurons. One prominent feature we observe is the extended pause time of QD-BDNF retrograde transport within Q140 striatal dendrites. Taken together, these finding support the hypothesis that delinquent spatiotemporal trophic support of BDNF to striatal neurons, driven by impaired transport, may contribute to the pathogenesis of HD, providing us with insight into how a BDNF supplementation therapeutic strategy may best be applied for HD.
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11
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Hassan SSU, Samanta S, Dash R, Karpiński TM, Habibi E, Sadiq A, Ahmadi A, Bungau S. The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress. Front Pharmacol 2022; 13:1015835. [PMID: 36299900 PMCID: PMC9589363 DOI: 10.3389/fphar.2022.1015835] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 09/08/2022] [Indexed: 12/13/2022] Open
Abstract
Oxidative stress (OS) disrupts the chemical integrity of macromolecules and increases the risk of neurodegenerative diseases. Fisetin is a flavonoid that exhibits potent antioxidant properties and protects the cells against OS. We have viewed the NCBI database, PubMed, Science Direct (Elsevier), Springer-Nature, ResearchGate, and Google Scholar databases to search and collect relevant articles during the preparation of this review. The search keywords are OS, neurodegenerative diseases, fisetin, etc. High level of ROS in the brain tissue decreases ATP levels, and mitochondrial membrane potential and induces lipid peroxidation, chronic inflammation, DNA damage, and apoptosis. The subsequent results are various neuronal diseases. Fisetin is a polyphenolic compound, commonly present in dietary ingredients. The antioxidant properties of this flavonoid diminish oxidative stress, ROS production, neurotoxicity, neuro-inflammation, and neurological disorders. Moreover, it maintains the redox profiles, and mitochondrial functions and inhibits NO production. At the molecular level, fisetin regulates the activity of PI3K/Akt, Nrf2, NF-κB, protein kinase C, and MAPK pathways to prevent OS, inflammatory response, and cytotoxicity. The antioxidant properties of fisetin protect the neural cells from inflammation and apoptotic degeneration. Thus, it can be used in the prevention of neurodegenerative disorders.
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Affiliation(s)
- Syed Shams ul Hassan
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- Department of Natural Product Chemistry, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Saptadip Samanta
- Department of Physiology, Midnapore College, Midnapore, West Bengal, India
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, South Korea
| | - Tomasz M. Karpiński
- Department of Medical Microbiology, Poznań University of Medical Sciences, Poznań, Poland
| | - Emran Habibi
- Department of Pharmacognosy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abdul Sadiq
- Department of Pharmacy, University of Malakand, Chakdara, Pakistan
| | - Amirhossein Ahmadi
- Pharmaceutical Sciences Research Centre, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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12
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Wang H, Del Mar N, Deng Y, Reiner A. Rescue of BDNF expression by the thalamic parafascicular nucleus with chronic treatment with the mGluR2/3 agonist LY379268 may contribute to the LY379268 rescue of enkephalinergic striatal projection neurons in R6/2 Huntington's disease mice. Neurosci Lett 2021; 763:136180. [PMID: 34416343 DOI: 10.1016/j.neulet.2021.136180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/13/2021] [Accepted: 08/14/2021] [Indexed: 10/20/2022]
Abstract
We have found that daily subcutaneous injection with a maximum tolerated dose of the mGluR2/3 agonist LY379268 (20 mg/kg) beginning at 4 weeks of age dramatically improves the motor, neuronal and neurochemical phenotype in R6/2 mice, a rapidly progressing transgenic model of Huntington's disease (HD). We also previously showed that the benefit of daily LY379268 in R6/2 mice was associated with increases in corticostriatal brain-derived neurotrophic factor (BDNF), and in particular was associated with a reduction in enkephalinergic striatal projection neuron loss. In the present study, we show that daily LY379268 also rescues expression of BDNF by neurons of the thalamic parafascicular nucleus in R6/2 mice, which projects prominently to the striatum, and this increase too is linked to the rescue of enkephalinergic striatal neurons. Thus, LY379268 may protect enkephalinergic striatal projection neurons from loss by boosting BDNF production and delivery via both the corticostriatal and thalamostriatal projection systems. These results suggest that chronic treatment with mGluR2/3 agonists may represent an approach for slowing enkephalinergic neuron loss in HD, and perhaps progression in general.
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Affiliation(s)
- H Wang
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
| | - N Del Mar
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
| | - Y Deng
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
| | - A Reiner
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States; Department of Ophthalmology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
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13
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Inhibition of GSK-3 ameliorates the pathogenesis of Huntington's disease. Neurobiol Dis 2021; 154:105336. [PMID: 33753290 DOI: 10.1016/j.nbd.2021.105336] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/10/2021] [Accepted: 03/17/2021] [Indexed: 12/22/2022] Open
Abstract
In Huntington's disease (HD), the mutant huntingtin (mHtt) accumulates as toxic aggregates in the striatum tissue, with deleterious effects on motor-coordination and cognitive functions. Reducing the levels of mHtt is therefore a promising therapeutic strategy. We have previously reported that GSK-3 is a negative regulator of the autophagy/lysosome pathway, which is responsible for intracellular degradation, and is critically important for maintaining neuronal vitality. Thus, we hypothesized that inhibition of GSK-3 may trigger mHtt clearance thereby reducing mHtt cytotoxicity and improving HD symptoms. Here, we demonstrate that depletion or suppression of autophagy results in a massive accumulation of mHtt aggregates. Accordingly, mHtt aggregates were localized in lysosomes, but, mostly mislocalized from lysosomes in the absence of functional autophagy. Overexpression of GSK-3, particularly the α isozyme, increased the number of mHtt aggregates, while silencing GSK-3α/β, or treatment with a selective GSK-3 inhibitor, L807mts, previously described by us, reduced the amounts of mHtt aggregates. This effect was mediated by increased autophagic and lysosomal activity. Treating R6/2 mouse model of HD with L807mts, reduced striatal mHtt aggregates and elevated autophagic and lysosomal markers. The L807mts treatment also reduced hyperglycemia and improved motor-coordination functions in these mice. In addition, L807mts restored the expression levels of Sirt1, a critical neuroprotective factor in the HD striatum, along with its targets BDNF, DRPP-32, and active Akt, all provide neurotrophic/pro-survival support and typically decline in the HD brain. Our results provide strong evidence for a role for GSK-3 in the regulation of mHtt dynamics, and demonstrate the benefits of GSK-3 inhibition in reducing mHtt toxicity, providing neuroprotective support, and improving HD symptoms.
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14
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Ou ZYA, Byrne LM, Rodrigues FB, Tortelli R, Johnson EB, Foiani MS, Arridge M, De Vita E, Scahill RI, Heslegrave A, Zetterberg H, Wild EJ. Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington's disease. Sci Rep 2021; 11:3481. [PMID: 33568689 PMCID: PMC7876124 DOI: 10.1038/s41598-021-83000-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/18/2021] [Indexed: 11/08/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington's disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.
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Affiliation(s)
- Zhen-Yi Andy Ou
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Lauren M Byrne
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Filipe B Rodrigues
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Rosanna Tortelli
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Eileanoir B Johnson
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Martha S Foiani
- UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK
| | - Marzena Arridge
- Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK
| | - Enrico De Vita
- Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, WC1N 3BG, UK
- Department of Biomedical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK
| | - Rachael I Scahill
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Amanda Heslegrave
- UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK
| | - Henrik Zetterberg
- UK Dementia Research Institute at UCL, London, WC1E 6BT, UK
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, 431 80, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden
| | - Edward J Wild
- UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
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Couly S, Carles A, Denus M, Benigno-Anton L, Maschat F, Maurice T. Exposure of R6/2 mice in an enriched environment augments P42 therapy efficacy on Huntington's disease progression. Neuropharmacology 2021; 186:108467. [PMID: 33516737 DOI: 10.1016/j.neuropharm.2021.108467] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 11/30/2022]
Abstract
Huntington's disease (HD) is due to a mutation in the gene encoding for Huntingtin protein generating polyQ domain extension. Mutant Htt (mHtt) leads to important dysfunction of the BDNF/TrkB signaling. We previously described the 23aa Htt fragment P42, that attenuated the pathological phenotypes induced by mHtt. We reported that, in the R6/2 mouse model of HD, P42 rescued striatal TrkB level but marginally increased cortical BDNF. In the present study, our aim was to address P42 neuroprotection in presence of an external input of BDNF. We combined P42 administration with environmental enrichment (EE), induced by training in the Hamlet test. We examined the consequences of P42 + EE combination on different phenotypes in R6/2 HD mice: motor and cognitive performances, recorded at early and late pathological stages, and analyzed aggregated mHtt and BDNF levels in forebrain structures. Hamlet exploration (i.e., entries in Run, Hide, Eat, Drink and Interact houses) was gradually impaired in R6/2 mice, but maintained by P42 treatment until week 8. Topographic memory alteration measured at week 7 was attenuated by P42. Motor performances (rotarod) were significantly ameliorated by the P42 + EE combination until late stage (week 12). The P42 + EE combination also significantly decreased aggregated Htt levels in the hippocampus, striatum and cortex, and increased BDNF levels in the cortex and striatum. We concluded that combination between P42 treatment, known to increase TrkB striatal expression, and a BDNF-enhancing therapy such as EE efficiently delayed HD pathology in R6/2 mice. Use of dual therapies might be a pertinent strategy to fight neurodegeneration in HD.
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Affiliation(s)
- Simon Couly
- MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France
| | - Allison Carles
- MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France
| | - Morgane Denus
- MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France
| | | | | | - Tangui Maurice
- MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France.
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16
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Al-Khafaji AH, Jepsen SD, Christensen KR, Vigsnæs LK. The potential of human milk oligosaccharides to impact the microbiota-gut-brain axis through modulation of the gut microbiota. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104176] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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17
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Induction of BDNF Expression in Layer II/III and Layer V Neurons of the Motor Cortex Is Essential for Motor Learning. J Neurosci 2020; 40:6289-6308. [PMID: 32651187 PMCID: PMC7424868 DOI: 10.1523/jneurosci.0288-20.2020] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 06/09/2020] [Accepted: 06/25/2020] [Indexed: 12/16/2022] Open
Abstract
Motor learning depends on synaptic plasticity between corticostriatal projections and striatal medium spiny neurons. Retrograde tracing from the dorsolateral striatum reveals that both layer II/III and V neurons in the motor cortex express BDNF as a potential regulator of plasticity in corticostriatal projections in male and female mice. The number of these BDNF-expressing cortical neurons and levels of BDNF protein are highest in juvenile mice when adult motor patterns are shaped, while BDNF levels in the adult are low. When mice are trained by physical exercise in the adult, BDNF expression in motor cortex is reinduced, especially in layer II/III projection neurons. Reduced expression of cortical BDNF in 3-month-old mice results in impaired motor learning while space memory is preserved. These findings suggest that activity regulates BDNF expression differentially in layers II/III and V striatal afferents from motor cortex and that cortical BDNF is essential for motor learning. SIGNIFICANCE STATEMENT Motor learning in mice depends on corticostriatal BDNF supply, and regulation of BDNF expression during motor learning is highest in corticostriatal projection neurons in cortical layer II/III.
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18
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Boloc D, Rodríguez N, Torres T, García-Cerro S, Parellada M, Saiz-Ruiz J, Cuesta MJ, Bernardo M, Gassó P, Lafuente A, Mas S, Arnaiz JA. Identifying key transcription factors for pharmacogenetic studies of antipsychotics induced extrapyramidal symptoms. Psychopharmacology (Berl) 2020; 237:2151-2159. [PMID: 32382784 DOI: 10.1007/s00213-020-05526-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 04/13/2020] [Indexed: 12/14/2022]
Abstract
INTRODUCTION We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies. METHODS Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP. RESULTS Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1. CONCLUSION Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.
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Affiliation(s)
- Daniel Boloc
- Department of Medicine, University of Barcelona, Barcelona, Spain
| | | | - Teresa Torres
- Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain
| | - Susana García-Cerro
- Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain
| | - Mara Parellada
- Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain
| | - Jeronimo Saiz-Ruiz
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain
- Hospital Ramon y Cajal, Universidad de Alcala, IRYCIS, Madrid, Spain
| | - Manuel J Cuesta
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain
- Department of Psychiatry, Complejo Hospitalario de Navarra. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Miquel Bernardo
- Department of Medicine, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain
- Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Spain The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Patricia Gassó
- Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain
- Spain The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Amalia Lafuente
- Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain
- Spain The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | - Sergi Mas
- Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Carlos III Health Institute, Madrid, Spain.
- Spain The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
| | - Joan Albert Arnaiz
- Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain.
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Gubert C, Renoir T, Hannan AJ. Why Woody got the blues: The neurobiology of depression in Huntington's disease. Neurobiol Dis 2020; 142:104958. [PMID: 32526274 DOI: 10.1016/j.nbd.2020.104958] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/02/2020] [Accepted: 06/03/2020] [Indexed: 02/03/2023] Open
Abstract
Huntington's disease (HD) is an extraordinary disorder that usually strikes when individuals are in the prime of their lives, as was the case for the influential 20th century musician Woody Guthrie. HD demonstrates the exceptionally fine line between life and death in such 'genetic diseases', as the only difference between those who suffer horribly and die slowly of this disease is often just a handful of extra tandem repeats (beyond the normal polymorphic range) in a genome that constitutes over 3 billion paired nucleotides of DNA. Furthermore, HD presents as a complex and heterogenous combination of psychiatric, cognitive and motor symptoms, so can appear as an unholy trinity of 'three disorders in one'. The autosomal dominant nature of the disorder is also extremely challenging for affected families, as a 'flip of a coin' dictates which children inherit the mutation from their affected parent, and the gene-negative family members bear the burden of caring for the other half of the family that is affected. In this review, we will focus on one of the earliest, and most devastating, symptoms associated with HD, depression, which has been reported to affect approximately half of gene-positive HD family members. We will discuss the pathogenesis of HD, and depressive symptoms in particular, including molecular and cellular mechanisms, and potential genetic and environmental modifiers. This expanding understanding of HD pathogenesis may not only lead to novel therapeutic options for HD families, but may also provide insights into depression in the wider population, which has the greatest burden of disease of any disorder and an enormous unmet need for new therapies.
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Affiliation(s)
- Carolina Gubert
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
| | - Thibault Renoir
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia
| | - Anthony J Hannan
- Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia; Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
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Kim HS, Jeon I, Noh JE, Lee H, Hong KS, Lee N, Pei Z, Song J. Intracerebral Transplantation of BDNF-overexpressing Human Neural Stem Cells (HB1.F3.BDNF) Promotes Migration, Differentiation and Functional Recovery in a Rodent Model of Huntington's Disease. Exp Neurobiol 2020; 29:130-137. [PMID: 32408403 PMCID: PMC7237270 DOI: 10.5607/en20011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/13/2020] [Accepted: 04/13/2020] [Indexed: 02/06/2023] Open
Abstract
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by abnormally expanded CAG repeats in the huntingtin gene. The huntingtin gene mutation leads to the progressive degeneration of striatal GABAergic medium spiny neurons (MSN) and reduces the level of brain-derived neurotrophic factor (BDNF) in HD patient's brain. BDNF is an essential neurotrophic factor for the cortico-striatal synaptic activity and the survival of GABAergic neurons. In this study, we transplanted BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) into the contra-lateral side of unilateral quinolinic acid (QA)-lesioned striatum of HD rat model. The results of in vivo transplantation were monitored using various behavioral tests, 4.7 T animal magnetic resonance imaging (MRI) and immunohistochemical staining. We observed that the QA-lesioned rats receiving HB1.F3.BDNF cells exhibited significant behavioral improvements in the stepping, rotarod and apomorphine-induced rotation tests. Interestingly, contralaterally transplanted cells were migrated to the QA-lesioned striatum and the size of lateral ventricle was reduced. Histological analyses further revealed that the transplanted cells, which had migrated to the QA lesion site, were differentiated into the cells of GABAergic, MSN-type neurons expressing DARPP-32, and neural networks were established between the transplanted cells and the host brain, as revealed by retrograde tracing. Finally, there was a significant reduction of inflammatory response in HB1.F3.BDNF-transplanted HD animal model, compared with vehicle-transplanted group. Taken together, these results suggest that HB1.F3.BDNF can be an effective therapeutic strategy to treat HD patients in the future.
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Affiliation(s)
- Hyun Sook Kim
- Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam 3496, Korea
| | - Iksoo Jeon
- CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea
| | - Jeong-Eun Noh
- CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea
| | - Hyunseung Lee
- Division of Magnetic Imaging Resonance, Korea Basic Science Institute, Cheongju 28119, Korea
| | - Kwan Soo Hong
- Division of Magnetic Imaging Resonance, Korea Basic Science Institute, Cheongju 28119, Korea
| | - Nayeon Lee
- CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea
| | - Zhong Pei
- Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affi liated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Jihwan Song
- CHA Stem Cell Institute, Department of Biomedical Science, CHA University, Seongnam 13488, Korea
- iPS Bio, Inc., Seongnam 1322, Korea
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21
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Tang BL. Could metformin be therapeutically useful in Huntington's disease? Rev Neurosci 2020; 31:297-317. [PMID: 31751298 DOI: 10.1515/revneuro-2019-0072] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 09/09/2019] [Indexed: 12/15/2022]
Abstract
Emerging evidence suggest that dimethylbiguanide (metformin), a first-line drug for type 2 diabetes mellitus, could be neuroprotective in a range of brain pathologies, which include neurodegenerative diseases and brain injury. However, there are also contraindications that associate metformin treatment with cognitive impairment as well as adverse outcomes in Alzheimer's disease and Parkinson's disease animal models. Recently, a beneficial effect of metformin in animal models of Huntington's disease (HD) has been strengthened by multiple reports. In this brief review, the findings associated with the effects of metformin in attenuating neurodegenerative diseases are discussed, focusing on HD-associated pathology and the potential underlying mechanisms highlighted by these studies. The mechanism of action of metformin is complex, and its therapeutic efficacy is therefore expected to be dependent on the disease context. The key metabolic pathways that are effectively affected by metformin, such as AMP-activated protein kinase activation, may be altered in the later decades of the human lifespan. In this regard, metformin may nonetheless be therapeutically useful for neurological diseases with early pathological onsets, such as HD.
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Affiliation(s)
- Bor Luen Tang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, Singapore 117596, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Medical Drive, Singapore 119077, Singapore
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22
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Blumenstock S, Dudanova I. Cortical and Striatal Circuits in Huntington's Disease. Front Neurosci 2020; 14:82. [PMID: 32116525 PMCID: PMC7025546 DOI: 10.3389/fnins.2020.00082] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/21/2020] [Indexed: 12/28/2022] Open
Abstract
Huntington's disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.
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Affiliation(s)
- Sonja Blumenstock
- Department of Molecules – Signaling – Development, Max Planck Institute of Neurobiology, Martinsried, Germany
- Molecular Neurodegeneration Group, Max Planck Institute of Neurobiology, Martinsried, Germany
| | - Irina Dudanova
- Molecular Neurodegeneration Group, Max Planck Institute of Neurobiology, Martinsried, Germany
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23
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Smith‐Dijak AI, Sepers MD, Raymond LA. Alterations in synaptic function and plasticity in Huntington disease. J Neurochem 2019; 150:346-365. [DOI: 10.1111/jnc.14723] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 03/28/2019] [Accepted: 05/08/2019] [Indexed: 12/27/2022]
Affiliation(s)
- Amy I. Smith‐Dijak
- Graduate Program in Neuroscience the University of British Columbia Vancouver British Columbia Canada
- Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health the University of British Columbia Vancouver British Columbia Canada
| | - Marja D. Sepers
- Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health the University of British Columbia Vancouver British Columbia Canada
| | - Lynn A. Raymond
- Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health the University of British Columbia Vancouver British Columbia Canada
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24
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Gangarossa G, Perez S, Dembitskaya Y, Prokin I, Berry H, Venance L. BDNF Controls Bidirectional Endocannabinoid Plasticity at Corticostriatal Synapses. Cereb Cortex 2019; 30:197-214. [DOI: 10.1093/cercor/bhz081] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 03/19/2019] [Accepted: 03/20/2019] [Indexed: 12/12/2022] Open
Abstract
AbstractThe dorsal striatum exhibits bidirectional corticostriatal synaptic plasticity, NMDAR and endocannabinoids (eCB) mediated, necessary for the encoding of procedural learning. Therefore, characterizing factors controlling corticostriatal plasticity is of crucial importance. Brain-derived neurotrophic factor (BDNF) and its receptor, the tropomyosine receptor kinase-B (TrkB), shape striatal functions, and their dysfunction deeply affects basal ganglia. BDNF/TrkB signaling controls NMDAR plasticity in various brain structures including the striatum. However, despite cross-talk between BDNF and eCBs, the role of BDNF in eCB plasticity remains unknown. Here, we show that BDNF/TrkB signaling promotes eCB-plasticity (LTD and LTP) induced by rate-based (low-frequency stimulation) or spike-timing–based (spike-timing–dependent plasticity, STDP) paradigm in striatum. We show that TrkB activation is required for the expression and the scaling of both eCB-LTD and eCB-LTP. Using 2-photon imaging of dendritic spines combined with patch-clamp recordings, we show that TrkB activation prolongs intracellular calcium transients, thus increasing eCB synthesis and release. We provide a mathematical model for the dynamics of the signaling pathways involved in corticostriatal plasticity. Finally, we show that TrkB activation enlarges the domain of expression of eCB-STDP. Our results reveal a novel role for BDNF/TrkB signaling in governing eCB-plasticity expression in striatum and thus the engram of procedural learning.
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Affiliation(s)
- Giuseppe Gangarossa
- Center for Interdisciplinary Research in Biology, College de France, Centre National de la Recherche Scientifique (CNRS) UMR, Institut National de la Santé et de la Recherche (INSERM), Paris Sciences et Lettres (PSL) Research University, Paris, France
| | - Sylvie Perez
- Center for Interdisciplinary Research in Biology, College de France, Centre National de la Recherche Scientifique (CNRS) UMR, Institut National de la Santé et de la Recherche (INSERM), Paris Sciences et Lettres (PSL) Research University, Paris, France
| | - Yulia Dembitskaya
- Center for Interdisciplinary Research in Biology, College de France, Centre National de la Recherche Scientifique (CNRS) UMR, Institut National de la Santé et de la Recherche (INSERM), Paris Sciences et Lettres (PSL) Research University, Paris, France
| | - Ilya Prokin
- INRIA, Villeurbanne, France
- University of Lyon, LIRIS UMR, Villeurbanne, France
| | - Hugues Berry
- INRIA, Villeurbanne, France
- University of Lyon, LIRIS UMR, Villeurbanne, France
| | - Laurent Venance
- Center for Interdisciplinary Research in Biology, College de France, Centre National de la Recherche Scientifique (CNRS) UMR, Institut National de la Santé et de la Recherche (INSERM), Paris Sciences et Lettres (PSL) Research University, Paris, France
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25
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Abstract
Polyglutamine (polyQ) diseases are a group of hereditary neurodegenerative disorders caused by expansion of unstable polyQ repeats in their associated disease proteins. To date, the pathogenesis of each disease remains poorly understood, and there are no effective treatments. Growing evidence has indicated that, in addition to neurodegeneration, polyQ-expanded proteins can cause a wide array of abnormalities in peripheral tissues. Indeed, polyQ-expanded proteins are ubiquitously expressed throughout the body and can affect the function of both the central nervous system (CNS) and peripheral tissues. The peripheral effects of polyQ disease proteins include muscle wasting and reduced muscle strength in patients or animal models of spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxia type 17 (SCA17). Since skeletal muscle pathology can reflect disease progression and is more accessible for treatment than neurodegeneration in the CNS, understanding how polyQ disease proteins affect skeletal muscle will help elucidate disease mechanisms and the development of new therapeutics. In this review, we focus on important findings in terms of skeletal muscle pathology in polyQ diseases and also discuss the potential mechanisms underlying the major peripheral effects of polyQ disease proteins, as well as their therapeutic implications.
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Affiliation(s)
- Shanshan Huang
- Department of Neurology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Suiqiang Zhu
- Department of Neurology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Jiang Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
| | - Shihua Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
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26
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Illarioshkin SN, Klyushnikov SA, Vigont VA, Seliverstov YA, Kaznacheyeva EV. Molecular Pathogenesis in Huntington's Disease. BIOCHEMISTRY. BIOKHIMIIA 2018; 83:1030-1039. [PMID: 30472941 DOI: 10.1134/s0006297918090043] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 05/31/2018] [Indexed: 01/04/2023]
Abstract
Huntington's disease (HD) is a severe autosomal dominant neurodegenerative disorder characterized by a combination of motor, cognitive, and psychiatric symptoms, atrophy of the basal ganglia and the cerebral cortex, and inevitably progressive course resulting in death 5-20 years after manifestation of its symptoms. HD is caused by expansion of CAG repeats in the HTT gene, which leads to pathological elongation of the polyglutamine tract within the respective protein - huntingtin. In this review, we present a modern view on molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. Main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as systemic failure of transcription, mitochondrial dysfunction and suppression of energy metabolism, abnormalities of cytoskeleton and axonal transport, microglial inflammation, decrease in synthesis of brain-derived neurotrophic factor, etc.
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Affiliation(s)
| | - S A Klyushnikov
- Research Center of Neurology, Moscow, 125367, Russia
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia
| | - V A Vigont
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
| | | | - E V Kaznacheyeva
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064, Russia.
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27
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Lieberman AP, Shakkottai VG, Albin RL. Polyglutamine Repeats in Neurodegenerative Diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2018; 14:1-27. [PMID: 30089230 DOI: 10.1146/annurev-pathmechdis-012418-012857] [Citation(s) in RCA: 196] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.
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Affiliation(s)
- Andrew P Lieberman
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
| | - Vikram G Shakkottai
- Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; , .,Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
| | - Roger L Albin
- Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; , .,Neurology Service and the Geriatric Research, Education, and Clinical Center (GRECC), VA Ann Arbor Healthcare System, Ann Arbor, Michigan 48105, USA
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28
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Simmons DA. Modulating Neurotrophin Receptor Signaling as a Therapeutic Strategy for Huntington's Disease. J Huntingtons Dis 2018; 6:303-325. [PMID: 29254102 PMCID: PMC5757655 DOI: 10.3233/jhd-170275] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the IT15 gene which encodes the huntingtin (HTT) protein. Currently, no treatments capable of preventing or slowing disease progression exist. Disease modifying therapeutics for HD would be expected to target a comprehensive set of degenerative processes given the diverse mechanisms contributing to HD pathogenesis including neuroinflammation, excitotoxicity, and transcription dysregulation. A major contributor to HD-related degeneration is mutant HTT-induced loss of neurotrophic support. Thus, neurotrophin (NT) receptors have emerged as therapeutic targets in HD. The considerable overlap between NT signaling networks and those dysregulated by mutant HTT provides strong theoretical support for this approach. This review will focus on the contributions of disrupted NT signaling in HD-related neurodegeneration and how targeting NT receptors to augment pro-survival signaling and/or to inhibit degenerative signaling may combat HD pathologies. Therapeutic strategies involving NT delivery, peptidomimetics, and the targeting of specific NT receptors (e.g., Trks or p75NTR), particularly with small molecule ligands, are discussed.
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Affiliation(s)
- Danielle A Simmons
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
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29
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Al-Ramahi I, Lu B, Di Paola S, Pang K, de Haro M, Peluso I, Gallego-Flores T, Malik NT, Erikson K, Bleiberg BA, Avalos M, Fan G, Rivers LE, Laitman AM, Diaz-García JR, Hild M, Palacino J, Liu Z, Medina DL, Botas J. High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration. Cell Syst 2018; 7:28-40.e4. [PMID: 29936182 PMCID: PMC6082401 DOI: 10.1016/j.cels.2018.05.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 02/14/2018] [Accepted: 05/16/2018] [Indexed: 01/17/2023]
Abstract
Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points.
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Affiliation(s)
- Ismael Al-Ramahi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Boxun Lu
- State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Life Sciences, Fudan University, Shanghai, China
| | - Simone Di Paola
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Kaifang Pang
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Maria de Haro
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Ivana Peluso
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Tatiana Gallego-Flores
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Nazish T Malik
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Kelly Erikson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Benjamin A Bleiberg
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Matthew Avalos
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - George Fan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Laura Elizabeth Rivers
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Andrew M Laitman
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Javier R Diaz-García
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Marc Hild
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - James Palacino
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Zhandong Liu
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Diego L Medina
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | - Juan Botas
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
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30
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Park H. Cortical Axonal Secretion of BDNF in the Striatum Is Disrupted in the Mutant-huntingtin Knock-in Mouse Model of Huntington's Disease. Exp Neurobiol 2018; 27:217-225. [PMID: 30022873 PMCID: PMC6050413 DOI: 10.5607/en.2018.27.3.217] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 05/23/2018] [Accepted: 05/25/2018] [Indexed: 01/24/2023] Open
Abstract
Deficient BDNF signaling is known to be involved in neurodegenerative diseases such as Huntington's disease (HD). Mutant huntingtin (mhtt)-mediated disruption of either BDNF transcription or transport is thought to be a factor contributing to striatal atrophy in the HD brain. Whether and how activity-dependent BDNF secretion is affected by the mhtt remains unclear. In the present study, I provide evidence for differential effects of the mhtt on cortical BDNF secretion in the striatum during HD progression. By two-photon imaging of fluorescent BDNF sensor (BDNF-pHluorin and -EGFP) in acute striatal slices of HD knock-in model mice, I found deficient cortical BDNF secretion regardless of the HD onset, but antisense oligonucleotide (ASO)-mediated reduction of htts only rescues BDNF secretion in the early HD brain before the disease onset. Although secretion modes of individual BDNF-containing vesicle were not altered in the pre-symptomatic brain, the full-fusion and partial-fusion modes of BDNF-containing vesicles were significantly altered after the onset of HD symptoms. Thus, besides abnormal BDNF transcription and transport, our results suggest that mhtt-mediated alteration in activity-dependent BDNF secretion at corticostriatal synapses also contributes to the development of HD.
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Affiliation(s)
- Hyungju Park
- Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA.,Molecular Neurobiology Lab, Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 41062, Korea
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31
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Pan Y, Zhu Y, Yang W, Tycksen E, Liu S, Palucki J, Zhu L, Sasaki Y, Sharma MK, Kim AH, Zhang B, Yano H. The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity. J Biol Chem 2018; 293:11850-11866. [PMID: 29891550 DOI: 10.1074/jbc.ra117.001211] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 05/14/2018] [Indexed: 01/12/2023] Open
Abstract
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the huntingtin protein (Htt). Transcriptional dysregulation is an early event in the course of HD progression and is thought to contribute to disease pathogenesis, but how mutant Htt causes transcriptional alterations and subsequent cell death in neurons is not well understood. RNA-Seq analysis revealed that expression of a mutant Htt fragment in primary cortical neurons leads to robust gene expression changes before neuronal death. Basic helix-loop-helix transcription factor Twist1, which is essential for embryogenesis and is normally expressed at low levels in mature neurons, was substantially up-regulated in mutant Htt-expressing neurons in culture and in the brains of HD mouse models. Knockdown of Twist1 by RNAi in mutant Htt-expressing primary cortical neurons reversed the altered expression of a subset of genes involved in neuronal function and, importantly, abrogated neurotoxicity. Using brain-derived neurotrophic factor (Bdnf), which is known to be involved in HD pathogenesis, as a model gene, we found that Twist1 knockdown could reverse mutant Htt-induced DNA hypermethylation at the Bdnf regulatory region and reactivate Bdnf expression. Together, these results suggest that Twist1 is an important upstream mediator of mutant Htt-induced neuronal death and may in part operate through epigenetic mechanisms.
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Affiliation(s)
| | - Ying Zhu
- From the Department of Neurological Surgery
| | - Wei Yang
- Genome Technology Access Center.,Department of Genetics
| | | | | | | | | | | | | | - Albert H Kim
- From the Department of Neurological Surgery.,Department of Genetics.,Department of Developmental Biology.,Center of Regenerative Medicine.,Department of Neurology, and.,Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Bo Zhang
- Department of Developmental Biology.,Center of Regenerative Medicine
| | - Hiroko Yano
- From the Department of Neurological Surgery, .,Department of Genetics.,Center of Regenerative Medicine.,Department of Neurology, and.,Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110
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32
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Lee M, Ban JJ, Chung JY, Im W, Kim M. Amelioration of Huntington's disease phenotypes by Beta-Lapachone is associated with increases in Sirt1 expression, CREB phosphorylation and PGC-1α deacetylation. PLoS One 2018; 13:e0195968. [PMID: 29742127 PMCID: PMC5942716 DOI: 10.1371/journal.pone.0195968] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 04/03/2018] [Indexed: 02/08/2023] Open
Abstract
Huntington’s disease (HD) is one of the most devastating genetic neurodegenerative disorders with no effective medical therapy. β-Lapachone (βL) is a natural compound obtained from the bark of the Lapacho tree and has been reported to have beneficial effects on various diseases. Sirt1 is a deacetylase of the sirtuin family and deacetylates proteins including the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) which is associated with mitochondrial respiration and biogenesis. To examine the effectiveness of βL on HD, βL was orally applied to R6/2 HD mice and behavioral phenotypes associated with HD, such as impairment of rota-rod performance and increase of clasping behavior, as well as changes of Sirt1 expression, CREB phosphorylation and PGC-1α deacetylation were examined. Western blot results showed that Sirt1 and p-CREB levels were significantly increased in the brains of βL-treated R6/2 mice. An increase in deacetylation of PGC-1α, which is thought to increase its activity, was observed by oral administration of βL. In an in vitro HD model, βL treatment resulted in an attenuation of MitoSOX red fluorescence intensity, indicating an amelioration of mitochondrial reactive oxygen species by βL. Furthermore, improvements in the rota-rod performance and clasping score were observed in R6/2 HD mice after oral administration of βL compared to that of vehicle control-treated mice. Taken together, our data show that βL is a potential therapeutic candidate for the treatment of HD-associated phenotypes, and increases in Sirt1 level, CREB phosphorylation and PGC-103B1 deacetylation can be the possible underlying mechanism of the effects of βL.
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Affiliation(s)
- Mijung Lee
- Department of Neurology, Seoul National University Hospital, Seoul, South Korea
| | - Jae-Jun Ban
- Department of Neurology, Seoul National University Hospital, Seoul, South Korea
| | - Jin-Young Chung
- Department of Veterinary Internal Medicine and Geriatrics, College of Veterinary Medicine, Kangwon National University, Gangwon, South Korea
| | - Wooseok Im
- Department of Neurology, Seoul National University Hospital, Seoul, South Korea
- Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- * E-mail: (WI); (MK)
| | - Manho Kim
- Department of Neurology, Seoul National University Hospital, Seoul, South Korea
- Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, South Korea
- Protein Metabolism Medical Research Center, College of Medicine, Seoul National University, Seoul, South Korea
- * E-mail: (WI); (MK)
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33
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Reiner A, Deng Y. Disrupted striatal neuron inputs and outputs in Huntington's disease. CNS Neurosci Ther 2018; 24:250-280. [PMID: 29582587 PMCID: PMC5875736 DOI: 10.1111/cns.12844] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 02/15/2018] [Accepted: 02/16/2018] [Indexed: 12/22/2022] Open
Abstract
Huntington's disease (HD) is a hereditary progressive neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the protein huntingtin, resulting in a pathogenic expansion of the polyglutamine tract in the N-terminus of this protein. The HD pathology resulting from the mutation is most prominent in the striatal part of the basal ganglia, and progressive differential dysfunction and loss of striatal projection neurons and interneurons account for the progression of motor deficits seen in this disease. The present review summarizes current understanding regarding the progression in striatal neuron dysfunction and loss, based on studies both in human HD victims and in genetic mouse models of HD. We review evidence on early loss of inputs to striatum from cortex and thalamus, which may be the basis of the mild premanifest bradykinesia in HD, as well as on the subsequent loss of indirect pathway striatal projection neurons and their outputs to the external pallidal segment, which appears to be the basis of the chorea seen in early symptomatic HD. Later loss of direct pathway striatal projection neurons and their output to the internal pallidal segment account for the severe akinesia seen late in HD. Loss of parvalbuminergic striatal interneurons may contribute to the late dystonia and rigidity.
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Affiliation(s)
- Anton Reiner
- Department of Anatomy & NeurobiologyThe University of Tennessee Health Science CenterMemphisTNUSA
- Department of OphthalmologyThe University of Tennessee Health Science CenterMemphisTNUSA
| | - Yun‐Ping Deng
- Department of Anatomy & NeurobiologyThe University of Tennessee Health Science CenterMemphisTNUSA
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34
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Victor MB, Richner M, Olsen HE, Lee SW, Monteys AM, Ma C, Huh CJ, Zhang B, Davidson BL, Yang XW, Yoo AS. Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes. Nat Neurosci 2018; 21:341-352. [PMID: 29403030 PMCID: PMC5857213 DOI: 10.1038/s41593-018-0075-7] [Citation(s) in RCA: 177] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 12/28/2017] [Indexed: 12/15/2022]
Abstract
In Huntington's disease (HD), expansion of CAG codons in the huntingtin gene (HTT) leads to the aberrant formation of protein aggregates and the differential degeneration of striatal medium spiny neurons (MSNs). Modeling HD using patient-specific MSNs has been challenging, as neurons differentiated from induced pluripotent stem cells are free of aggregates and lack an overt cell death phenotype. Here we generated MSNs from HD patient fibroblasts through microRNA-based direct neuronal conversion, bypassing the induction of pluripotency and retaining age signatures of the original fibroblasts. We found that patient MSNs consistently exhibited mutant HTT (mHTT) aggregates, mHTT-dependent DNA damage, mitochondrial dysfunction and spontaneous degeneration in culture over time. We further provide evidence that erasure of age stored in starting fibroblasts or neuronal conversion of presymptomatic HD patient fibroblasts results in differential manifestation of cellular phenotypes associated with HD, highlighting the importance of age in modeling late-onset neurological disorders.
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Affiliation(s)
- Matheus B Victor
- Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Graduate Program in Neuroscience, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA
| | - Michelle Richner
- Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Hannah E Olsen
- Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Seong Won Lee
- Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Alejandro M Monteys
- The Raymond G Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Chunyu Ma
- Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Christine J Huh
- Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Bo Zhang
- Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Beverly L Davidson
- The Raymond G Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology & Laboratory Medicine, The University of Pennsylvania, Philadelphia, PA, USA
| | - X William Yang
- Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Andrew S Yoo
- Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.
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35
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García-Díaz Barriga G, Giralt A, Anglada-Huguet M, Gaja-Capdevila N, Orlandi JG, Soriano J, Canals JM, Alberch J. 7,8-dihydroxyflavone ameliorates cognitive and motor deficits in a Huntington's disease mouse model through specific activation of the PLCγ1 pathway. Hum Mol Genet 2018; 26:3144-3160. [PMID: 28541476 DOI: 10.1093/hmg/ddx198] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 05/17/2017] [Indexed: 01/08/2023] Open
Abstract
Huntington's disease (HD) is a fatal neurodegenerative disease with motor, cognitive and psychiatric impairment. Dysfunctions in HD models have been related to reduced levels of striatal brain-derived neurotrophic factor (BDNF) and imbalance between its receptors TrkB and p75(NTR). Thus, molecules with activity on the BDNF/TrkB/p75 system can have therapeutic potential. 7,8-Dihydroxyflavone (7,8-DHF) was described as a TrkB agonist in several models of neuro-degenerative diseases, however, its TrkB activation profile needs further investigation due to its pleiotropic properties and divergence from BDNF effect. To investigate this, we used in vitro and in vivo models of HD to dissect TrkB activation upon 7,8-DHF treatment. 7,8-DHF treatment in primary cultures showed phosphorylation of TrkBY816 but not TrkBY515 with activation of the PLCγ1 pathway leading to morphological and functional improvements. Chronic administration of 7,8-DHF delayed motor deficits in R6/1 mice and reversed deficits on the Novel Object Recognition Test (NORT) at 17 weeks. Morphological and biochemical analyses revealed improved striatal levels of enkephalin, and prevention of striatal volume loss. We found a TrkBY816 but not TrkBY515 phosphorylation recovery in striatum concordant with in vitro results. Additionally, 7,8-DHF normalized striatal levels of induced and neuronal nitric oxide synthase (iNOS and nNOS, respectively) and ameliorated the imbalance of p75/TrkB. Our results provide new insights into the mechanism of action of 7,8-DHF suggesting that its effect through the TrkB receptor in striatum is via selective phosphorylation of its Y816 residue and activation of PLCγ1 pathway, but pleiotropic effects of the drug also contribute to its therapeutic potential.
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Affiliation(s)
- Gerardo García-Díaz Barriga
- Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Albert Giralt
- Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Marta Anglada-Huguet
- Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Nuria Gaja-Capdevila
- Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Javier G Orlandi
- Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Jordi Soriano
- Departament de Física de la Matèria Condensada, Universitat de Barcelona, Barcelona, Spain.,Institute of Complex Systems (UBICS), Universitat de Barcelona, Barcelona, Spain
| | - Josep-Maria Canals
- Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Jordi Alberch
- Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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36
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Dragatsis I, Dietrich P, Ren H, Deng YP, Del Mar N, Wang HB, Johnson IM, Jones KR, Reiner A. Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum. Neurobiol Dis 2017; 111:102-117. [PMID: 29274742 PMCID: PMC5821111 DOI: 10.1016/j.nbd.2017.12.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 11/07/2017] [Accepted: 12/19/2017] [Indexed: 12/12/2022] Open
Abstract
We evaluated the impact of early embryonic deletion of huntingtin (htt) from pyramidal neurons on cortical development, cortical neuron survival and motor behavior, using a cre-loxP strategy to inactivate the mouse htt gene (Hdh) in emx1-expressing cell lineages. Western blot confirmed substantial htt reduction in cerebral cortex of these Emx-httKO mice, with residual cortical htt in all likelihood restricted to cortical interneurons of the subpallial lineage and/or vascular endothelial cells. Despite the loss of htt early in development, cortical lamination was normal, as revealed by layer-specific markers. Cortical volume and neuron abundance were, however, significantly less than normal, and cortical neurons showed reduced brain-derived neurotrophic factor (BDNF) expression and reduced activation of BDNF signaling pathways. Nonetheless, cortical volume and neuron abundance did not show progressive age-related decline in Emx-httKO mice out to 24 months. Although striatal neurochemistry was normal, reductions in striatal volume and neuron abundance were seen in Emx-httKO mice, which were again not progressive. Weight maintenance was normal in Emx-httKO mice, but a slight rotarod deficit and persistent hyperactivity were observed throughout the lifespan. Our results show that embryonic deletion of htt from developing pallium does not substantially alter migration of cortical neurons to their correct laminar destinations, but does yield reduced cortical and striatal size and neuron numbers. The Emx-httKO mice were persistently hyperactive, possibly due to defects in corticostriatal development. Importantly, deletion of htt from cortical pyramidal neurons did not yield age-related progressive cortical or striatal pathology.
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Affiliation(s)
- I Dragatsis
- Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - P Dietrich
- Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - H Ren
- Department of Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - Y P Deng
- Department of Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - N Del Mar
- Department of Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - H B Wang
- Department of Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - I M Johnson
- Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States
| | - K R Jones
- Department of Molecular, Cellular, & Developmental Biology, 347 UCB, University of Colorado, Boulder, CO 80309, United States
| | - A Reiner
- Department of Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States; Department of Ophthalmology, The University of Tennessee Health Science Center, Memphis, TN 38163, United States.
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37
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Reidling JC, Relaño-Ginés A, Holley SM, Ochaba J, Moore C, Fury B, Lau A, Tran AH, Yeung S, Salamati D, Zhu C, Hatami A, Cepeda C, Barry JA, Kamdjou T, King A, Coleal-Bergum D, Franich NR, LaFerla FM, Steffan JS, Blurton-Jones M, Meshul CK, Bauer G, Levine MS, Chesselet MF, Thompson LM. Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice. Stem Cell Reports 2017; 10:58-72. [PMID: 29233555 PMCID: PMC5768890 DOI: 10.1016/j.stemcr.2017.11.005] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 11/03/2017] [Accepted: 11/03/2017] [Indexed: 01/01/2023] Open
Abstract
Huntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF) in both models. These findings hold promise for future development of stem cell-based therapies.
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Affiliation(s)
- Jack C Reidling
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Aroa Relaño-Ginés
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Sandra M Holley
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
| | - Joseph Ochaba
- Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Cindy Moore
- Portland VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA
| | - Brian Fury
- Institute for Regenerative Cures, University of California, Davis, 2921 Stockton Boulevard, Sacramento, CA 95817, USA
| | - Alice Lau
- Department of Psychiatry & Human Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Andrew H Tran
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Sylvia Yeung
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Delaram Salamati
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Chunni Zhu
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Asa Hatami
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Carlos Cepeda
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
| | - Joshua A Barry
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
| | - Talia Kamdjou
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
| | - Alvin King
- Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Dane Coleal-Bergum
- Institute for Regenerative Cures, University of California, Davis, 2921 Stockton Boulevard, Sacramento, CA 95817, USA
| | - Nicholas R Franich
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Frank M LaFerla
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Joan S Steffan
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Psychiatry & Human Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA
| | - Mathew Blurton-Jones
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Sue and Bill Gross Stem Cell Center, University of California, Irvine, Gross Hall, Room 3219, 845 Health Sciences Road, Irvine, CA 92697, USA
| | - Charles K Meshul
- Portland VA Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA; Oregon Health & Science University, Department of Behavioral Neuroscience, 3181 SW Sam Jackson Park Road, L470, Portland, OR 97239, USA
| | - Gerhard Bauer
- Institute for Regenerative Cures, University of California, Davis, 2921 Stockton Boulevard, Sacramento, CA 95817, USA
| | - Michael S Levine
- Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA; Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90095, USA
| | - Marie-Francoise Chesselet
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA
| | - Leslie M Thompson
- Institute for Memory Impairment and Neurological Disorders, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Neurobiology & Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Department of Psychiatry & Human Behavior, University of California, Irvine, 3400 Biological Sciences III, Irvine, CA 92697-4545, USA; Sue and Bill Gross Stem Cell Center, University of California, Irvine, Gross Hall, Room 3219, 845 Health Sciences Road, Irvine, CA 92697, USA.
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38
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Al-Gharaibeh A, Culver R, Stewart AN, Srinageshwar B, Spelde K, Frollo L, Kolli N, Story D, Paladugu L, Anwar S, Crane A, Wyse R, Maiti P, Dunbar GL, Rossignol J. Induced Pluripotent Stem Cell-Derived Neural Stem Cell Transplantations Reduced Behavioral Deficits and Ameliorated Neuropathological Changes in YAC128 Mouse Model of Huntington's Disease. Front Neurosci 2017; 11:628. [PMID: 29209158 PMCID: PMC5701605 DOI: 10.3389/fnins.2017.00628] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 10/27/2017] [Indexed: 01/01/2023] Open
Abstract
Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by neuronal loss and motor dysfunction. Although there is no effective treatment, stem cell transplantation offers a promising therapeutic strategy, but the safety and efficacy of this approach needs to be optimized. The purpose of this study was to test the potential of intra-striatal transplantation of induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) for treating HD. For this purpose, we developed mouse adenovirus-generated iPSCs, differentiated them into neural stem cells in vitro, labeled them with Hoechst, and transplanted them bilaterally into striata of 10-month old wild type (WT) and HD YAC128 mice. We assessed the efficiency of these transplanted iPS-NSCs to reduce motor deficits in YAC128 mice by testing them on an accelerating rotarod task at 1 day prior to transplantation, and then weekly for 10 weeks. Our results showed an amelioration of locomotor deficits in YAC128 mice that received iPS-NSC transplantations. Following testing, the mice were sacrificed, and their brains were analyzed using immunohistochemistry and Western blot (WB). The results from our histological examinations revealed no signs of tumors and evidence that many iPS-NSCs survived and differentiated into region-specific neurons (medium spiny neurons) in both WT and HD mice, as confirmed by co-labeling of Hoechst-labeled transplanted cells with NeuN and DARPP-32. Also, counts of Hoechst-labeled cells revealed that a higher proportion were co-labeled with DARPP-32 and NeuN in HD-, compared to WT- mice, suggesting a dissimilar differentiation pattern in HD mice. Whereas significant decreases were found in counts of NeuN- and DARPP-32-labeled cells, and for neuronal density measures in striata of HD vehicle controls, such decrements were not observed in the iPS-NSCs-transplanted-HD mice. WB analysis showed increase of BDNF and TrkB levels in striata of transplanted HD mice compared to HD vehicle controls. Collectively, our data suggest that iPS-NSCs may provide an effective option for neuronal replacement therapy in HD.
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Affiliation(s)
- Abeer Al-Gharaibeh
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Rebecca Culver
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Andrew N Stewart
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Bhairavi Srinageshwar
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Kristin Spelde
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Laura Frollo
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Nivya Kolli
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Darren Story
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States.,Department of Psychology, Central Michigan University, Mount Pleasant, MI, United States
| | - Leela Paladugu
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States
| | - Sarah Anwar
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States
| | - Andrew Crane
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States
| | - Robert Wyse
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States
| | - Panchanan Maiti
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States.,Department of Psychology, Central Michigan University, Mount Pleasant, MI, United States.,Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, United States
| | - Gary L Dunbar
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States.,Department of Psychology, Central Michigan University, Mount Pleasant, MI, United States.,Field Neurosciences Institute, St. Mary's of Michigan, Saginaw, MI, United States
| | - Julien Rossignol
- Field Neurosciences Institute Laboratory for Restorative Neurology, Central Michigan University, Mount Pleasant, MI, United States.,Program in Neuroscience, Central Michigan University, Mount Pleasant, MI, United States.,College of Medicine, Central Michigan University, Mt Pleasant, MI, United States
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39
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Veldman MB, Yang XW. Molecular insights into cortico-striatal miscommunications in Huntington's disease. Curr Opin Neurobiol 2017; 48:79-89. [PMID: 29125980 DOI: 10.1016/j.conb.2017.10.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 10/18/2017] [Indexed: 12/12/2022]
Abstract
Huntington's disease (HD), a dominantly inherited neurodegenerative disease, is defined by its genetic cause, a CAG-repeat expansion in the HTT gene, its motor and psychiatric symptomology and primary loss of striatal medium spiny neurons (MSNs). However, the molecular mechanisms from genetic lesion to disease phenotype remain largely unclear. Mouse models of HD have been created that exhibit phenotypes partially recapitulating those in the patient, and specifically, cortico-striatal disconnectivity appears to be a shared pathogenic event shared by HD mouse models and patients. Molecular studies have begun to unveil converging molecular and cellular pathogenic mechanisms that may account for cortico-striatal miscommunication in various HD mouse models. Systems biological approaches help to illuminate synaptic molecular networks as a nexus for HD cortio-striatal pathogenesis, and may offer new candidate targets to modify the disease.
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Affiliation(s)
- Matthew B Veldman
- Center for Neurobehavioral Genetics and Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
| | - X William Yang
- Center for Neurobehavioral Genetics and Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States.
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40
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Yang JW, Ma W, Yang YL, Wang XB, Li XT, Wang TT, Wang XP, Gao W, Li JY, Zhou XF, Guo JH, Li LY. Region-specific expression of precursor and mature brain-derived neurotrophic factors after chronic alcohol exposure. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2017; 43:602-608. [PMID: 28032807 DOI: 10.1080/00952990.2016.1263642] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 11/14/2016] [Accepted: 11/17/2016] [Indexed: 01/14/2023]
Abstract
BACKGROUND Alcohol abuse is a serious health problem worldwide that causes a variety of physical and mental disorders. Research has shown that the brain-derived neurotrophic factor (BDNF) plays an important role in alcohol addiction. The BDNF precursor (proBDNF) exhibits different actions than BDNF through separate receptors and pathways in the central nervous system. However, the effects of proBDNF and BDNF in alcohol addiction are not fully known. OBJECTIVES The objective was to identify the expression patterns and effects of proBDNF and BDNF after chronic alcohol exposure. METHODS A total of 40 male adult mice were studied. A mouse psychomotor sensitization (PS) model was established to explore the effects of BDNF and proBDNF treatment following chronic alcohol exposure. Reverse transcription PCR (RT-PCR) was performed to measure mRNA levels for BDNF, TrkB, P75NTR, and sortilin in the prefrontal cortex, hippocampus, and dorsal striatum of Kunming mice after chronic alcohol exposure. RESULTS In Kunming mice, chronic alcohol exposure up-regulated BDNF and TrkB mRNA levels in the prefrontal cortex, but decreased sortilin and P75 mRNA levels in the dorsal striatum. No changes in mRNA levels were found in other measured brain regions in the alcohol and control groups. CONCLUSION Chronic alcohol exposure induced the region-specific expression of BDNF and proBDNF and their respective receptors in the brain. These results suggest that BDNF and proBDNF signaling pathways may play major roles in alcohol preference and addiction.
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Affiliation(s)
- Jin-Wei Yang
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
- b Second Department of General Surgery , First People's Hospital of Yunnan Province , Yunnan Kunming , China
| | - Wei Ma
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
| | - Yan-Lei Yang
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
- c First People's Hospital of Honghe State , Yunnan Mengzi , China
| | - Xian-Bin Wang
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
| | - Xing-Tong Li
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
| | - Tong-Tong Wang
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
| | - Xiang-Peng Wang
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
- d Department of Neurosurgery , First Affiliated Hospital of Kunming Medical University , Yunnan Kunming , China
| | - Wei Gao
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
| | - Jun-Yan Li
- e Department of Neurosurgery , First People's Hospital of Kunming City , Yunnan Kunming , China
| | - Xin-Fu Zhou
- f School of Pharmacy and Medical Sciences, Sansom Institute, Faculty of Health Sciences , University of South Australia , Adelaide , Australia
| | - Jian-Hui Guo
- b Second Department of General Surgery , First People's Hospital of Yunnan Province , Yunnan Kunming , China
| | - Li-Yan Li
- a Institute of Neuroscience , Kunming Medical University , Yunnan Kunming , China
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Liot G, Valette J, Pépin J, Flament J, Brouillet E. Energy defects in Huntington's disease: Why “in vivo” evidence matters. Biochem Biophys Res Commun 2017; 483:1084-1095. [DOI: 10.1016/j.bbrc.2016.09.065] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 09/13/2016] [Indexed: 01/12/2023]
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Mitre M, Mariga A, Chao MV. Neurotrophin signalling: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 2017; 131:13-23. [PMID: 27908981 PMCID: PMC5295469 DOI: 10.1042/cs20160044] [Citation(s) in RCA: 184] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 07/18/2016] [Accepted: 08/09/2016] [Indexed: 12/29/2022]
Abstract
Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are prominent regulators of neuronal survival, growth and differentiation during development. While trophic factors are viewed as well-understood but not innovative molecules, there are many lines of evidence indicating that BDNF plays an important role in the pathophysiology of many neurodegenerative disorders, depression, anxiety and other psychiatric disorders. In particular, lower levels of BDNF are associated with the aetiology of Alzheimer's and Huntington's diseases. A major challenge is to explain how neurotrophins are able to induce plasticity, improve learning and memory and prevent age-dependent cognitive decline through receptor signalling. This article will review the mechanism of action of neurotrophins and how BDNF/tropomyosin receptor kinase B (TrkB) receptor signaling can dictate trophic responses and change brain plasticity through activity-dependent stimulation. Alternative approaches for modulating BDNF/TrkB signalling to deliver relevant clinical outcomes in neurodegenerative and neuropsychiatric disorders will also be described.
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Affiliation(s)
- Mariela Mitre
- Neuroscience and Physiology and Psychiatry, New York University School of Medicine, New York, NY 10016, U.S.A.
- Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, U.S.A
| | - Abigail Mariga
- Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, U.S.A
- Departments of Cell Biology, New York University School of Medicine, New York, NY 10016, U.S.A
| | - Moses V Chao
- Neuroscience and Physiology and Psychiatry, New York University School of Medicine, New York, NY 10016, U.S.A
- Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, U.S.A
- Departments of Cell Biology, New York University School of Medicine, New York, NY 10016, U.S.A
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Mariga A, Mitre M, Chao MV. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease. Neurobiol Dis 2017; 97:73-79. [PMID: 27015693 PMCID: PMC5295364 DOI: 10.1016/j.nbd.2016.03.009] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 02/20/2016] [Accepted: 03/09/2016] [Indexed: 01/07/2023] Open
Abstract
Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease.
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Affiliation(s)
- Abigail Mariga
- Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, United States; Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY, 10016, United States
| | - Mariela Mitre
- Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, 10016, United States; Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY, 10016, United States
| | - Moses V Chao
- Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, United States; Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, 10016, United States; Department of Psychiatry, New York University School of Medicine, New York, NY, 10016, United States; Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY, 10016, United States
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Lokhande S, Patra BN, Ray A. A link between chromatin condensation mechanisms and Huntington's disease: connecting the dots. MOLECULAR BIOSYSTEMS 2016; 12:3515-3529. [PMID: 27714015 DOI: 10.1039/c6mb00598e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Huntington's disease is a rare neurodegenerative disorder whose complex pathophysiology exhibits system-wide changes in the body, with striking and debilitating clinical features targeting the central nervous system. Among the various molecular functions affected in this disease, mitochondrial dysfunction and transcriptional dysregulation are some of the most studied aspects of this disease. However, there is evidence of the involvement of a mutant Huntingtin protein in the processes of DNA damage, chromosome condensation and DNA repair. This review attempts to briefly recapitulate the clinical features, model systems used to study the disease, major molecular processes affected, and, more importantly, examines recent evidence for the involvement of the mutant Huntingtin protein in the processes regulating chromosome condensation, leading to DNA damage response and neuronal death.
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Affiliation(s)
- Sonali Lokhande
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA 91711, USA.
| | - Biranchi N Patra
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA 91711, USA.
| | - Animesh Ray
- Keck Graduate Institute of Applied Life Sciences, Claremont, CA 91711, USA.
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45
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Ring KL, An MC, Zhang N, O'Brien RN, Ramos EM, Gao F, Atwood R, Bailus BJ, Melov S, Mooney SD, Coppola G, Ellerby LM. Genomic Analysis Reveals Disruption of Striatal Neuronal Development and Therapeutic Targets in Human Huntington's Disease Neural Stem Cells. Stem Cell Reports 2016; 5:1023-1038. [PMID: 26651603 PMCID: PMC4682390 DOI: 10.1016/j.stemcr.2015.11.005] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 11/02/2015] [Accepted: 11/12/2015] [Indexed: 12/29/2022] Open
Abstract
We utilized induced pluripotent stem cells (iPSCs) derived from Huntington's disease (HD) patients as a human model of HD and determined that the disease phenotypes only manifest in the differentiated neural stem cell (NSC) stage, not in iPSCs. To understand the molecular basis for the CAG repeat expansion-dependent disease phenotypes in NSCs, we performed transcriptomic analysis of HD iPSCs and HD NSCs compared to isogenic controls. Differential gene expression and pathway analysis pointed to transforming growth factor β (TGF-β) and netrin-1 as the top dysregulated pathways. Using data-driven gene coexpression network analysis, we identified seven distinct coexpression modules and focused on two that were correlated with changes in gene expression due to the CAG expansion. Our HD NSC model revealed the dysregulation of genes involved in neuronal development and the formation of the dorsal striatum. The striatal and neuronal networks disrupted could be modulated to correct HD phenotypes and provide therapeutic targets.
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Affiliation(s)
- Karen L Ring
- Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Mahru C An
- Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Ningzhe Zhang
- Buck Institute for Research on Aging, Novato, CA 94945, USA
| | | | - Eliana Marisa Ramos
- Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Fuying Gao
- Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Robert Atwood
- Buck Institute for Research on Aging, Novato, CA 94945, USA
| | | | - Simon Melov
- Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Sean D Mooney
- Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Giovanni Coppola
- Departments of Neurology and Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - Lisa M Ellerby
- Buck Institute for Research on Aging, Novato, CA 94945, USA.
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TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington's disease. Proc Natl Acad Sci U S A 2016; 113:E5655-64. [PMID: 27601642 DOI: 10.1073/pnas.1603020113] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Corticostriatal atrophy is a cardinal manifestation of Huntington's disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons.
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Pan Y, Daito T, Sasaki Y, Chung YH, Xing X, Pondugula S, Swamidass SJ, Wang T, Kim AH, Yano H. Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity. Sci Rep 2016; 6:31022. [PMID: 27516062 PMCID: PMC4981892 DOI: 10.1038/srep31022] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
Although epigenetic abnormalities have been described in Huntington's disease (HD), the causal epigenetic mechanisms driving neurodegeneration in HD cortex and striatum remain undefined. Using an epigenetic pathway-targeted drug screen, we report that inhibitors of DNA methyltransferases (DNMTs), decitabine and FdCyd, block mutant huntingtin (Htt)-induced toxicity in primary cortical and striatal neurons. In addition, knockdown of DNMT3A or DNMT1 protected neurons against mutant Htt-induced toxicity, together demonstrating a requirement for DNMTs in mutant Htt-triggered neuronal death and suggesting a neurodegenerative mechanism based on DNA methylation-mediated transcriptional repression. Inhibition of DNMTs in HD model primary cortical or striatal neurons restored the expression of several key genes, including Bdnf, an important neurotrophic factor implicated in HD. Accordingly, the Bdnf promoter exhibited aberrant cytosine methylation in mutant Htt-expressing cortical neurons. In vivo, pharmacological inhibition of DNMTs in HD mouse brains restored the mRNA levels of key striatal genes known to be downregulated in HD. Thus, disturbances in DNA methylation play a critical role in mutant Htt-induced neuronal dysfunction and death, raising the possibility that epigenetic strategies targeting abnormal DNA methylation may have therapeutic utility in HD.
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Affiliation(s)
- Yanchun Pan
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Takuji Daito
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yo Sasaki
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yong Hee Chung
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Xiaoyun Xing
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Santhi Pondugula
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - S. Joshua Swamidass
- Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ting Wang
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Albert H. Kim
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
- Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Hiroko Yano
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
- Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, MO 63110, USA
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Trehalose rescues glial cell dysfunction in striatal cultures from HD R6/1 mice at early postnatal development. Mol Cell Neurosci 2016; 74:128-45. [DOI: 10.1016/j.mcn.2016.05.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 03/29/2016] [Accepted: 05/24/2016] [Indexed: 12/31/2022] Open
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Deng YP, Reiner A. Cholinergic interneurons in the Q140 knockin mouse model of Huntington's disease: Reductions in dendritic branching and thalamostriatal input. J Comp Neurol 2016; 524:3518-3529. [PMID: 27219491 DOI: 10.1002/cne.24013] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/29/2016] [Accepted: 04/06/2016] [Indexed: 12/19/2022]
Abstract
We have previously found that thalamostriatal axodendritic terminals are reduced as early as 1 month of age in heterozygous Q140 HD mice (Deng et al. [] Neurobiol Dis 60:89-107). Because cholinergic interneurons are a major target of thalamic axodendritic terminals, we examined the VGLUT2-immunolabeled thalamic input to striatal cholinergic interneurons in heterozygous Q140 males at 1 and 4 months of age, using choline acetyltransferase (ChAT) immunolabeling to identify cholinergic interneurons. Although blinded neuron counts showed that ChAT+ perikarya were in normal abundance in Q140 mice, size measurements indicated that they were significantly smaller. Sholl analysis further revealed the dendrites of Q140 ChAT+ interneurons were significantly fewer and shorter. Consistent with the light microscopic data, ultrastructural analysis showed that the number of ChAT+ dendritic profiles per unit area of striatum was significantly decreased in Q140 striata, as was the abundance of VGLUT2+ axodendritic terminals making synaptic contact with ChAT+ dendrites per unit area of striatum. The density of thalamic terminals along individual cholinergic dendrites was, however, largely unaltered, indicating that the reduction in the areal striatal density of axodendritic thalamic terminals on cholinergic neurons was due to their dendritic territory loss. These results show that the abundance of thalamic input to individual striatal cholinergic interneurons is reduced early in the life span of Q140 mice, raising the possibility that this may occur in human HD as well. Because cholinergic interneurons differentially affect striatal direct vs. indirect pathway spiny projection neurons, their reduced thalamic excitatory drive may contribute to early abnormalities in movement in HD. J. Comp. Neurol. 524:3518-3529, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Yun-Ping Deng
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, 38163
| | - Anton Reiner
- Department of Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, 38163.
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50
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Deng P, Anderson JD, Yu AS, Annett G, Fink KD, Nolta JA. Engineered BDNF producing cells as a potential treatment for neurologic disease. Expert Opin Biol Ther 2016; 16:1025-33. [PMID: 27159050 DOI: 10.1080/14712598.2016.1183641] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Brain-derived neurotrophic factor (BDNF) has been implicated in wide range of neurological diseases and injury. This neurotrophic factor is vital for neuronal health, survival, and synaptic connectivity. Many therapies focus on the restoration or enhancement of BDNF following injury or disease progression. AREAS COVERED The present review will focus on the mechanisms in which BDNF exerts its beneficial functioning, current BDNF therapies, issues and potential solutions for delivery of neurotrophic factors to the central nervous system, and other disease indications that may benefit from overexpression or restoration of BDNF. EXPERT OPINION Due to the role of BDNF in neuronal development, maturation, and health, BDNF is implicated in numerous neurological diseases making it a prime therapeutic agent. Numerous studies have shown the therapeutic potential of BDNF in a number of neurodegenerative disease models and in acute CNS injury, however clinical translation has fallen short due to issues in delivering this molecule. The use of MSC as a delivery platform for BDNF holds great promise for clinical advancement of neurotrophic factor restoration. The ease with which MSC can be engineered opens the door to the possibility of using this cell-based delivery system to advance a BDNF therapy to the clinic.
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Affiliation(s)
- Peter Deng
- a Stem Cell Program and Institute for Regenerative Cures , University of California Davis Health Systems , Sacramento , CA , USA.,b Genome Center, MIND Institute, and Biochemistry and Molecular Medicine , University of California , Davis , CA , USA
| | - Johnathon D Anderson
- a Stem Cell Program and Institute for Regenerative Cures , University of California Davis Health Systems , Sacramento , CA , USA
| | - Abigail S Yu
- b Genome Center, MIND Institute, and Biochemistry and Molecular Medicine , University of California , Davis , CA , USA
| | - Geralyn Annett
- a Stem Cell Program and Institute for Regenerative Cures , University of California Davis Health Systems , Sacramento , CA , USA
| | - Kyle D Fink
- a Stem Cell Program and Institute for Regenerative Cures , University of California Davis Health Systems , Sacramento , CA , USA
| | - Jan A Nolta
- a Stem Cell Program and Institute for Regenerative Cures , University of California Davis Health Systems , Sacramento , CA , USA
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