|
1
|
Zhang Y, Du B, Zou M, Peng B, Rao Y. Neuronal Ceroid Lipofuscinosis-Concepts, Classification, and Avenues for Therapy. CNS Neurosci Ther 2025; 31:e70261. [PMID: 39925015 PMCID: PMC11808193 DOI: 10.1111/cns.70261] [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: 10/18/2024] [Revised: 01/26/2025] [Accepted: 01/28/2025] [Indexed: 02/11/2025] Open
Abstract
Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation of lysosomal lipofuscin. Thirteen subtypes of NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory proteins, or lysosomal enzymes. Clinically, NCL manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, and premature death. The pathological complexity of NCL has hindered the development of effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene therapy, and stem cell therapy, have demonstrated limited efficacy. However, emerging evidence suggests a significant relationship between NCL and microglial cells, highlighting the potential of novel microglial cell replacement therapies. This review comprehensively examines the pathogenic genes associated with various NCL subtypes, elucidating their roles, clinical presentations, and corresponding mouse models. Especially, we thoroughly discuss the advances in the clinical study of potential therapeutics, which crucially calls for early diagnosis and treatment more than ever.
Collapse
Affiliation(s)
- Yuheng Zhang
- Department of Neurology, Zhongshan Hospital, Laboratory Animal CenterFudan UniversityShanghaiChina
- Children’s Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory DiseasesFudan UniversityShanghaiChina
| | - Bingying Du
- Children’s Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory DiseasesFudan UniversityShanghaiChina
- Department of NeurologyThe First Affiliated Hospital of Naval Medical UniversityShanghaiChina
| | - Miaozhan Zou
- Department of Neurology, Zhongshan Hospital, Laboratory Animal CenterFudan UniversityShanghaiChina
- Children’s Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory DiseasesFudan UniversityShanghaiChina
| | - Bo Peng
- Children’s Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory DiseasesFudan UniversityShanghaiChina
| | - Yanxia Rao
- Department of Neurology, Zhongshan Hospital, Laboratory Animal CenterFudan UniversityShanghaiChina
| |
Collapse
|
|
2
|
Mandalawatta HP, Rajendra K, Fairfax K, Hewitt AW. Emerging trends in virus and virus-like particle gene therapy delivery to the brain. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102280. [PMID: 39206077 PMCID: PMC11350507 DOI: 10.1016/j.omtn.2024.102280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Recent advances in gene therapy and gene-editing techniques offer the very real potential for successful treatment of neurological diseases. However, drug delivery constraints continue to impede viable therapeutic interventions targeting the brain due to its anatomical complexity and highly restrictive microvasculature that is impervious to many molecules. Realizing the therapeutic potential of gene-based therapies requires robust encapsulation and safe and efficient delivery to the target cells. Although viral vectors have been widely used for targeted delivery of gene-based therapies, drawbacks such as host genome integration, prolonged expression, undesired off-target mutations, and immunogenicity have led to the development of alternative strategies. Engineered virus-like particles (eVLPs) are an emerging, promising platform that can be engineered to achieve neurotropism through pseudotyping. This review outlines strategies to improve eVLP neurotropism for therapeutic brain delivery of gene-editing agents.
Collapse
Affiliation(s)
| | - K.C. Rajendra
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
| | - Kirsten Fairfax
- School of Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Alex W. Hewitt
- Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
- School of Medicine, University of Tasmania, Hobart, TAS, Australia
| |
Collapse
|
|
3
|
Mitsui S, Yamaguchi J, Suzuki C, Uchiyama Y, Tanida I. TUNEL-positive structures in activated microglia and SQSTM1/p62-positive structures in activated astrocytes in the neurodegenerative brain of a CLN10 mouse model. Glia 2023; 71:2753-2769. [PMID: 37571859 DOI: 10.1002/glia.24449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/28/2023] [Accepted: 07/20/2023] [Indexed: 08/13/2023]
Abstract
Neuronal ceroid lipofuscinosis is a group of pediatric neurodegenerative diseases. One of their causative genes, CLN10/CtsD, encodes cathepsin D, a major lysosomal protease. Central nervous system (CNS)-specific CtsD-deficient mice exhibit a neurodegenerative disease phenotype with accumulation of ceroid lipofuscins, granular osmiophilic deposits, and SQSTM1/p62. We focused on activated astrocytes and microglia in this neurodegenerative mouse brain, since there are few studies on the relationship between these accumulators and lysosomes in these glial cells. Activated microglia and astrocytes in this mouse thalamus at p24 were increased by approximately 2.5- and 4.6-fold compared with the control, while neurons were decreased by approximately half. Granular osmiophilic deposits were detected in microglial cell bodies and extended their processes in the thalamus. LAMP1-positive lysosomes, but not SQSTM1/p62 aggregates, accumulated in microglia of this mouse thalamus, whereas both lysosomes and SQSTM1/p62 aggregates accumulated in its astrocytes. TUNEL-positive signals were observed mainly in microglia, but few were observed in neurons and astrocytes. These signals were fragmented DNA from degenerated neurons engulfed by microglia or in the lysosomes of microglia. Abnormal autophagic vacuoles also accumulated in the lysosomes of microglia. Granular osmiophilic deposit-like structures localized to LAMP1-positive lysosomes in CtsD-deficient astrocytes. SQSTM1/p62-positive but LAMP1-negative membranous structures also accumulated in the astrocytes and were less condensed than typical granular osmiophilic deposits. These results suggest that CtsD deficiency leads to intracellular abnormalities in activated microglia and astrocytes in addition to neuronal degeneration.
Collapse
Affiliation(s)
- Shun Mitsui
- Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Junji Yamaguchi
- Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Laboratory of Morphology and Image Analysis, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Chigure Suzuki
- Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuo Uchiyama
- Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Isei Tanida
- Department of Cellular and Molecular Neuropathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| |
Collapse
|
|
4
|
Panjeshahi S, Karimzadeh P, Movafagh A, Ahmadabadi F, Rahimian E, Alijanpour S, Miryounesi M. Clinical and genetic characterization of neuronal ceroid lipofuscinoses (NCLs) in 29 Iranian patients: identification of 11 novel mutations. Hum Genet 2023; 142:1001-1016. [PMID: 37074398 DOI: 10.1007/s00439-023-02556-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 04/10/2023] [Indexed: 04/20/2023]
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative lysosomal storage diseases which are considered among the most frequent causes of dementia in childhood worldwide This study aimed to identify the gene variants, molecular etiologies, and clinical features in 23 unrelated Iranian families with NCL. In total, 29 patients with neuronal ceroid lipofuscinoses (NCLs), diagnosed based on clinical manifestations, MRI neuroimaging, and electroencephalography (EEG), were recruited for this study. Through whole-exome sequencing (WES), functional prediction, Sanger sequencing, and segregation analysis, we found that 12 patients (41.3%) with mutations in the CLN6 gene, 7 patients (24%) with the TPP1 (CLN2) gene variants, and 4 patients (13.7%) with mutations in the MFSD8 (CLN7) gene. Also, mutations in each of the CLN3 and CLN5 genes were detected in 2 cases and mutations of each PPT1 (CLN1) and CLN8 gene were observed in only 1 separate patient. We identified 18 different mutations, 11 (61%) of which are novel, never have been reported before, and the others have been previously described. The gene variants identified in this study expand the number of published clinical cases and the variant frequency spectrum of the neuronal ceroid lipofuscinoses (NCLs) genes; moreover, the identification of these variants supplies foundational clues for future NCL diagnosis and therapy.
Collapse
Affiliation(s)
- Samareh Panjeshahi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvaneh Karimzadeh
- Pediatric Neurology Research Center, Pediatric Neurology Department, Mofid Children's Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Movafagh
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Ahmadabadi
- Pediatric Neurology Research Center, Pediatric Neurology Department, Mofid Children's Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Sahar Alijanpour
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Miryounesi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
5
|
Wang XQ, Chen CB, Zhao WJ, Fu GB, Zhai Y. Rare adult neuronal ceroid lipofuscinosis associated with CLN6 gene mutations: A case report. World J Clin Cases 2023; 11:3533-3541. [PMID: 37383919 PMCID: PMC10294197 DOI: 10.12998/wjcc.v11.i15.3533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/06/2023] [Accepted: 04/13/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Adult neuronal ceroid lipofuscinosis (ANCL) can be caused by compound heterozygous recessive mutations in CLN6. The main clinical features of the disease are neurodegeneration, progressive motor dysfunction, seizures, cognitive decline, ataxia, vision loss and premature death.
CASE SUMMARY A 37-year-old female presented to our clinic with a 3-year history of limb weakness and gradually experiencing unstable walking. The patient was diagnosed with CLN6 type ANCL after the identification of mutations in the CLN6 gene. The patient was treated with antiepileptic drugs. The patient is under ongoing follow-up. Unfortunately, the patient’s condition has deteriorated, and she is currently unable to care for herself.
CONCLUSION There is presently no effective treatment for ANCL. However, early diagnosis and symptomatic treatment are possible.
Collapse
Affiliation(s)
- Xue-Qiang Wang
- Department of Neurology, Sanya People’s Hospital, West China (Sanya) Hospital, Sichuan University, Sanya 572000, Hainan Province, China
| | - Chuan-Bi Chen
- Department of Pediatrics, Sanya Women and Children’s Hospital Managed by Shanghai Children's Medical Center, Sanya 572000, Hainan Province, China
| | - Wen-Jie Zhao
- Department of Neurology, The First Affiliated Hospital of Hainan Medical College, Haikou 570100, Hainan Province, China
| | - Guang-Bin Fu
- Department of Neurology, Hainan Western Central Hospital, Danzhou 571799, Hainan Province, China
| | - Yu Zhai
- Department of Neurology, Hainan Western Central Hospital, Danzhou 571799, Hainan Province, China
| |
Collapse
|
|
6
|
Purzycka-Olewiecka JK, Hetmańczyk-Sawicka K, Kmieć T, Szczęśniak D, Trubicka J, Krawczyński M, Pronicki M, Ługowska A. Deterioration of visual quality and acuity as the first sign of ceroid lipofuscinosis type 3 (CLN3), a rare neurometabolic disease. Metab Brain Dis 2023; 38:709-715. [PMID: 36576693 PMCID: PMC9859910 DOI: 10.1007/s11011-022-01148-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 12/14/2022] [Indexed: 12/29/2022]
Abstract
Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of 'fingerprints' and vacuolized lymphocytes suggest the diagnosis of CLN3. Cause of CLN3 are mutations in the CLN3 gene, among which the most frequently found is the large deletion 1.02 kb spreading on exons 7 and 8. We present 4 patients from 2 families, in whom the deterioration of visual quality and acuity was observed as first clinical sign, when they were a few years old and it was successively accompanied by symptoms of neurologic deterioration (like generalized convulsions with consciousness impairment). In all patients the 1.02 kb deletion in the CLN3 gene was detected in homo- or heterozygosity with other CLN3 pathogenic variant. Ultrastructural studies revealed abnormal structures corresponding to 'fingerprint' profiles (FPPs) in conjunctival endothelial cells. It should be emphasized that in patients with blindness of unknown cause the diagnosis of ceroid lipofuscinosis should be considered and in older children-especially CLN3. The facility of the analysis for the presence of 1.02 kb deletion and economic costs are a solid argument for intensive use of this test in the diagnostic procedure of CLN3.
Collapse
Affiliation(s)
| | | | - Tomasz Kmieć
- Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dominika Szczęśniak
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Joanna Trubicka
- Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland
| | - Maciej Krawczyński
- Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland
- Center for Medical Genetics GENESIS, Poznan, Poland
| | - Maciej Pronicki
- Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland
| | - Agnieszka Ługowska
- Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
| |
Collapse
|
|
7
|
Lee J, Xu Y, Saidi L, Xu M, Zinsmaier K, Ye Y. Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated DNAJC5/CSPα mutants causes lipofuscin accumulation. Autophagy 2023; 19:204-223. [PMID: 35506243 PMCID: PMC9809949 DOI: 10.1080/15548627.2022.2065618] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/05/2022] [Accepted: 04/08/2022] [Indexed: 01/09/2023] Open
Abstract
Mutations in DNAJC5/CSPα are associated with adult neuronal ceroid lipofuscinosis (ANCL), a dominant-inherited neurodegenerative disease featuring lysosome-derived autofluorescent storage materials (AFSMs) termed lipofuscin. Functionally, DNAJC5 has been implicated in chaperoning synaptic proteins and in misfolding-associated protein secretion (MAPS), but how DNAJC5 dysfunction causes lipofuscinosis and neurodegeneration is unclear. Here we report two functionally distinct but coupled chaperoning activities of DNAJC5, which jointly regulate lysosomal homeostasis: While endolysosome-associated DNAJC5 promotes ESCRT-dependent microautophagy, a fraction of perinuclear and non-lysosomal DNAJC5 mediates MAPS. Functional proteomics identifies a previously unknown DNAJC5 interactor SLC3A2/CD98hc that is essential for the perinuclear DNAJC5 localization and MAPS but dispensable for microautophagy. Importantly, uncoupling these two processes, as seen in cells lacking SLC3A2 or expressing ANCL-associated DNAJC5 mutants, generates DNAJC5-containing AFSMs resembling NCL patient-derived lipofuscin and induces neurodegeneration in a Drosophila ANCL model. These findings suggest that MAPS safeguards microautophagy to avoid DNAJC5-associated lipofuscinosis and neurodegeneration.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AFSM: autofluorescent storage materials; ANCL: adult neuronal ceroid lipofuscinosis; Baf. A1: bafilomycin A1; CLN: ceroid lipofuscinosis neuronal; CLU: clusterin; CS: cysteine string domain of DNAJC5/CSPα; CUPS: compartment for unconventional protein secretion; DN: dominant negative; DNAJC5/CSPα: DnaJ heat shock protein family (Hsp40) member C5; eMI: endosomal microautophagy; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; INCL: infant neuronal ceroid lipofuscinosis; JNCL: juvenile neuronal ceroid lipofuscinosis; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAPTM4B: lysosomal protein transmembrane 4 beta; LN: linker domain of DNAJC5/CSPα; MAPS: misfolding-associated protein secretion; mCh/Ch: mCherry; mCi/Ci: mCitrine; MTOR: mechanistic target of rapamycin kinase; NCL: neuronal ceroid lipofuscinosis; PPT1: palmitoyl-protein thioesterase 1; PQC: protein quality control; SBP: streptavidin binding protein; SGT: small glutamine-rich tetratricopeptide repeat; shRNA: short hairpin RNA; SLC3A2/CD98hc: solute carrier family 3 member 2; SNCA/α-synuclein: synuclein alpha; TMED10: transmembrane p24 trafficking protein 10; UV: ultraviolet; VPS4: vacuolar protein sorting 4 homolog; WT: wild type.
Collapse
Affiliation(s)
- Juhyung Lee
- Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yue Xu
- Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Layla Saidi
- Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Miao Xu
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Konrad Zinsmaier
- Departments of Neuroscience and Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA
| | - Yihong Ye
- Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
8
|
Kashyap SN, Boyle NR, Roberson ED. Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations. Neurotherapeutics 2023; 20:140-153. [PMID: 36781744 PMCID: PMC10119358 DOI: 10.1007/s13311-023-01348-6] [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] [Accepted: 01/20/2023] [Indexed: 02/15/2023] Open
Abstract
Heterozygous loss-of-function mutations in progranulin (GRN) cause frontotemporal dementia (FTD), a leading cause of early-onset dementia characterized clinically by behavioral, social, and language deficits. There are currently no FDA-approved therapeutics for FTD-GRN, but this has been an active area of investigation, and several approaches are now in clinical trials. Here, we review preclinical development of therapies for FTD-GRN with a focus on testing in mouse models. Since most FTD-GRN-associated mutations cause progranulin haploinsufficiency, these approaches focus on raising progranulin levels. We begin by considering the disorders associated with altered progranulin levels, and then review the basics of progranulin biology including its lysosomal, neurotrophic, and immunomodulatory functions. We discuss mouse models of progranulin insufficiency and how they have been used in preclinical studies on a variety of therapeutic approaches. These include approaches to raise progranulin expression from the normal allele or facilitate progranulin production by the mutant allele, as well as approaches to directly increase progranulin levels by delivery across the blood-brain barrier or by gene therapy. Several of these approaches have entered clinical trials, providing hope that new therapies for FTD-GRN may be the next frontier in the treatment of neurodegenerative disease.
Collapse
Affiliation(s)
- Shreya N Kashyap
- Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Medical Scientist Training Program, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Nicholas R Boyle
- Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Medical Scientist Training Program, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Erik D Roberson
- Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, Medical Scientist Training Program, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
| |
Collapse
|
|
9
|
Huang L, Zhang Z. CSPα in neurodegenerative diseases. Front Aging Neurosci 2022; 14:1043384. [DOI: 10.3389/fnagi.2022.1043384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/17/2022] [Indexed: 11/19/2022] Open
Abstract
Adult-onset neuronal ceroid lipofuscinosis (ANCL) is a rare neurodegenerative disease characterized by epilepsy, cognitive degeneration, and motor disorders caused by mutations in the DNAJC5 gene. In addition to being associated with ANCL disease, the cysteine string proteins α (CSPα) encoded by the DNAJC5 gene have been implicated in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. However, the pathogenic mechanism responsible for these neurodegenerative diseases has not yet been elucidated. Therefore, this study examines the functional properties of the CSPα protein and the related mechanisms of neurodegenerative diseases.
Collapse
|
|
10
|
Thirumal Kumar D, Shaikh N, Udhaya Kumar S, George Priya Doss C. Computational and structural investigation of Palmitoyl-Protein Thioesterase 1 (PPT1) protein causing Neuronal Ceroid Lipofuscinoses (NCL). ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2022; 132:89-109. [PMID: 36088080 DOI: 10.1016/bs.apcsb.2022.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The Neuronal Ceroid Lipofuscinoses (NCL) are a group of progressive neurodegenerative disorders, associated with 14 Ceroid Lipofuscinosis Neuronal genes (CLN1-14). The mutations in the Palmitoyl-Protein Thioesterase 1 (PPT1) protein serve as one of the major reasons for the causative of NCL. The PPT1 involves degrading and modifying cysteine residues in proteins or peptides by removing thioester-linked fatty acyl groups like palmitate prefers acyl chains of 14-18 carbons in length. In this study, we have analyzed the impact of PPT1 mutations on the deleteriousness, stability, conservative nature of amino acid, and impact of mutations on the protein structure. We have also used molecular dynamics simulations using GROMACS to perceive the alteration in the dynamic behavior of the PPT1 at the residual level. In this study, we have retrieved 23 PPT1 mutations from the UniProt database, and these were subjected to a series of analyses using varied computer algorithms. From these analyses, out of 23 mutations, 16 mutations were identified as deleterious. Among 16, eight mutations were identified to destabilize the protein structure, and finally, two mutations (W38C and L222P) were found to be positioned in the highly conserved region. The structural impact study observed that the mutant proline could disrupt the alpha helix formed by the leucine at position 222. Finally, from the molecular dynamics simulations, we observed that due to the mutations (W38C and L222P), the protein had experienced higher deviation, fluctuation, and lower compactness. These structural changes elucidate that these mutations can impact the structure and function of the PPT1 protein.
Collapse
Affiliation(s)
- D Thirumal Kumar
- Faculty of Allied Health Sciences, Meenakshi Academy of Higher Education and Research, Chennai, Tamil Nadu, India.
| | - Nishaat Shaikh
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - S Udhaya Kumar
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India
| | - C George Priya Doss
- Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India.
| |
Collapse
|
|
11
|
Lee J, Xu Y, Ye Y. Safeguarding Lysosomal Homeostasis by DNAJC5/CSPα-Mediated Unconventional Protein Secretion and Endosomal Microautophagy. Front Cell Dev Biol 2022; 10:906453. [PMID: 35620055 PMCID: PMC9127312 DOI: 10.3389/fcell.2022.906453] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/25/2022] [Indexed: 11/24/2022] Open
Abstract
Neuronal ceroid lipofuscinosis (NCL) is a collection of genetically inherited neurological disorders characterized by vision loss, seizure, brain death, and premature lethality. At the cellular level, a key pathologic hallmark of NCL is the build-up of autofluorescent storage materials (AFSM) in lysosomes of both neurons and non-neuronal cells. Molecular dissection of the genetic lesions underlying NCLs has shed significant insights into how disruption of lysosomal homeostasis may lead to lipofuscin accumulation and NCLs. Intriguingly, recent studies on DNAJC5/CSPα, a membrane associated HSC70 co-chaperone, have unexpectedly linked lipofuscin accumulation to two intimately coupled protein quality control processes at endolysosomes. This review discusses how deregulation of unconventional protein secretion and endosomal microautophagy (eMI) contributes to lipofuscin accumulation and neurodegeneration.
Collapse
Affiliation(s)
| | | | - Yihong Ye
- Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| |
Collapse
|
|
12
|
Simonati A, Williams RE. Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview. Front Neurol 2022; 13:811686. [PMID: 35359645 PMCID: PMC8961688 DOI: 10.3389/fneur.2022.811686] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/11/2022] [Indexed: 01/04/2023] Open
Abstract
The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis (NCL), a group of rare neurodegenerative disorders. These are genetic diseases associated with the formation of toxic endo-lysosomal storage. Following a brief historical review of the evolution of NCL definition, a clinically-oriented approach is used describing how the early symptoms and signs affecting motor, visual, cognitive domains, and including seizures, may lead clinicians to a rapid molecular diagnosis, avoiding the long diagnostic odyssey commonly observed. We go on to focus on recent advances in NCL research and summarize contributions to knowledge of the pathogenic mechanisms underlying NCL. We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. The search for innovative therapies is described. Translation of experimental data into therapeutic approaches is being established for several of the NCLs, and one drug is now commercially available. Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions.
Collapse
Affiliation(s)
- Alessandro Simonati
- Departments of Surgery, Dentistry, Paediatrics, and Gynaecology, School of Medicine, University of Verona, Verona, Italy
- Department of Clinical Neuroscience, AOUI-VR, Verona, Italy
- *Correspondence: Alessandro Simonati
| | - Ruth E. Williams
- Department of Children's Neuroscience, Evelina London Children's Hospital, London, United Kingdom
- Ruth E. Williams
| |
Collapse
|
|
13
|
Gultekin M, Tufekcioglu Z, Baydemir R. Novel frameshift CTSF mutation causing kufs disease type B mimicking frontotemporal dementia-parkinsonism. Neurocase 2022; 28:107-109. [PMID: 35139754 DOI: 10.1080/13554794.2022.2038635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Adult-onset neuronal ceroid lipofuscinoses (ANCLs, Kufs disease-KD) are rare, inherited, progressive, neurodegenerative, lysosomal storage diseases. Mutations in cathepsin F (CTSF) were linked to KD type B. Conversely, Frontotemporal dementia (FTD) is the second most common type of presenile dementia and Parkinsonism is a mostly common accompanying feature. Due to pronounced behavioral, cognitive, and motor features in the patients with KD type B, mutations in CTSF may resemble FTD-parkinsonism. Here, we present a case of KD type B with a novel homozygous frameshift pathogenic variant (p.Gly439Alafs*36) in the Cathepsin F (CTSF) gene presenting behavioral changes, cognitive disturbances and parkinsonism with a family history mimicking FTD-parkinsonism.
Collapse
Affiliation(s)
- Murat Gultekin
- Department of Neurology, M.D. Erciyes University, Kayseri, Turkey
| | | | - Recep Baydemir
- Department of Neurology, Erciyes University, Kayseri, Turkey
| |
Collapse
|
|
14
|
Francelle L, Mazzulli JR. Neuroinflammation in aucher disease, neuronal ceroid lipofuscinosis, and commonalities with Parkinson’s disease. Brain Res 2022; 1780:147798. [PMID: 35063468 PMCID: PMC9126024 DOI: 10.1016/j.brainres.2022.147798] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 01/05/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022]
Abstract
Lysosomal storage diseases (LSDs) are rare genetic disorders caused by a disruption in cellular clearance, resulting in pathological storage of undegraded lysosomal substrates. Recent clinical and genetic studies have uncovered links between multiple LSDs and common neurodegenerative diseases such as Parkinson's disease (PD). Here, we review recent literature describing the role of glia cells and neuroinflammation in PD and LSDs, including Gaucher disease (GD) and neuronal ceroid lipofuscinosis (NCL), and highlight converging inflammation pathways that lead to neuron loss. Recent data indicates that lysosomal dysfunction and accumulation of storage materials can initiate the activation of glial cells, through interaction with cell surface or cytosolic pattern recognition receptors that detect pathogenic aggregates of cellular debris. Activated glia cells could act to protect neurons through the elimination of toxic protein or lipid aggregates early in the disease process. However prolonged glial activation that occurs over several decades in chronic-age related neurodegeneration could induce the inappropriate elimination of synapses, leading to neuron loss. These studies provide mechanistic insight into the relationship between lysosomal dysfunction and glial activation, and offer novel therapeutic pathways for the treatment of PD and LSDs focused on reducing neuroinflammation and mitigating cell loss.
Collapse
|
|
15
|
Franco G, Lazzeri G, Di Fonzo A. Parkinsonism and ataxia. J Neurol Sci 2021; 433:120020. [PMID: 34711421 DOI: 10.1016/j.jns.2021.120020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/09/2021] [Accepted: 09/29/2021] [Indexed: 11/17/2022]
Abstract
Ataxia is not a common feature in Parkinson's disease. Nevertheless, some rare forms of parkinsonism have ataxia as one of the main features in their clinical picture, especially those with juvenile or early-onset. On the other side, in cerebellar degenerative diseases, parkinsonism might accompany the typical symptoms and even become predominant in some cases. Many disorders involving different neurological systems present with a movement phenomenology reflecting the underlying pattern of pathological involvement, such as neurodegeneration with brain iron accumulation, neurodegeneration associated with calcium deposition, and metabolic and mitochondrial disorders. The prototype of sporadic disorders that present with a constellation of symptoms due to the involvement of multiple Central Nervous System regions is multiple system atrophy, whose motor symptoms at onset can be cerebellar ataxia or parkinsonism. Clinical syndromes encompassing both parkinsonian and cerebellar features might represent a diagnostic challenge for neurologists. Recognizing acquired and potentially treatable causes responsible for complex movement disorders is of paramount importance, since an early diagnosis is essential to prevent permanent consequences. The present review aims to provide a pragmatic overview of the most common diseases characterized by the coexistence of cerebellar and parkinsonism features and suggests a possible diagnostic approach for both inherited and sporadic disorders. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.
Collapse
Affiliation(s)
- Giulia Franco
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
| | - Giulia Lazzeri
- Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Alessio Di Fonzo
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.
| |
Collapse
|
|
16
|
Talbot J, Singh P, Puvirajasinghe C, Sisodiya SM, Rugg-Gunn F. Moyamoya and progressive myoclonic epilepsy secondary to CLN6 bi-allelic mutations - A previously unreported association. Epilepsy Behav Rep 2020; 14:100389. [PMID: 33024953 PMCID: PMC7528204 DOI: 10.1016/j.ebr.2020.100389] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/29/2020] [Accepted: 08/01/2020] [Indexed: 12/26/2022] Open
Abstract
The neuronal ceroid lipofuscinoses (NCL) are a collection of lysosomal storage diseases characterised by the accumulation of characteristic inclusions containing lipofuscin in various tissues of the body and are one of the causes of progressive myoclonic epilepsy. Mutations in at least thirteen genes have been identified as causes of NCL, which can present as infantile, late-infantile, juvenile or adult forms. CLN6 codes for an endoplasmic reticulum transmembrane protein of unknown function. Homozygous and compound heterozygous mutations of the gene are associated with both late-infantile (LINCL) and adult onset (ANCL) forms of NCL, including Kufs disease, comprising ANCL without associated visual loss. Moyamoya, a rare vasculopathy of the circle of Willis, has been reported in conjunction with a number of inflammatory and other diseases, as well as a handful of lysosomal storage diseases. To our knowledge, this is the first reported case of Moyamoya in the context of the neuronal ceroid lipofuscinoses or a CLN6-related disease.
Collapse
Key Words
- ANCL
- ANCL, adult neuronal ceroid lipofuscinosis
- BMIPB, the Brain Injury Rehabilitation Trust Memory and Information Processing Battery
- CLN6
- Kufs disease
- LINCL, late-infantile neuronal ceroid lipofuscinosis
- MERRF, mitochondrial epilepsy with ragged red fibres
- Moyamoya
- NCL
- NCL, neuronal ceroid lipofuscinosis
- Neuronal ceroid lipofuscinosis
- PPT1, palmitoyl-protein thioesterase 1
- SEP, somatosensory evoked potentials
- TPP1, tripeptidyl peptidase 1
- WAIS-IV, Wechsler Adult Intelligence Scale (4th edition)
- Wiegl, Weigl Color Form Sorting Test
- mtDNA, mitochondrial DNA
Collapse
Affiliation(s)
- Jamie Talbot
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK
| | - Priyanka Singh
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK
| | - Clinda Puvirajasinghe
- Rare & Inherited Disease Laboratory, North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, Levels 4-6 Barclay House, 37, Queen Square, London WC1N 3BH, UK
| | | | - Sanjay M Sisodiya
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK
| | - Fergus Rugg-Gunn
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK
| |
Collapse
|
|
17
|
Jedličková I, Cadieux-Dion M, Přistoupilová A, Stránecký V, Hartmannová H, Hodaňová K, Barešová V, Hůlková H, Sikora J, Nosková L, Mušálková D, Vyleťal P, Sovová J, Cossette P, Andermann E, Andermann F, Kmoch S. Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing. Eur J Hum Genet 2020; 28:783-789. [PMID: 31919451 PMCID: PMC7253421 DOI: 10.1038/s41431-019-0567-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 11/29/2019] [Accepted: 12/10/2019] [Indexed: 11/09/2022] Open
Abstract
Adult-onset neuronal ceroid lipofuscinoses (ANCL, Kufs disease) are rare hereditary neuropsychiatric disorders characterized by intralysosomal accumulation of ceroid in tissues. The ceroid accumulation primarily affects the brain, leading to neuronal loss and progressive neurodegeneration. Although several causative genes have been identified (DNAJC5, CLN6, CTSF, GRN, CLN1, CLN5, ATP13A2), the genetic underpinnings of ANCL in some families remain unknown. Here we report one family with autosomal dominant (AD) Kufs disease caused by a 30 bp in-frame duplication in DNAJC5, encoding the cysteine-string protein alpha (CSPα). This variant leads to a duplication of the central core motif of the cysteine-string domain of CSPα and affects palmitoylation-dependent CSPα sorting in cultured neuronal cells similarly to two previously described CSPα variants, p.(Leu115Arg) and p.(Leu116del). Interestingly, the duplication was not detected initially by standard Sanger sequencing due to a preferential PCR amplification of the shorter wild-type allele and allelic dropout of the mutated DNAJC5 allele. It was also missed by subsequent whole-exome sequencing (WES). Its identification was facilitated by reanalysis of original WES data and modification of the PCR and Sanger sequencing protocols. Independently occurring variants in the genomic sequence of DNAJC5 encoding the cysteine-string domain of CSPα suggest that this region may be more prone to DNA replication errors and that insertions or duplications within this domain should be considered in unsolved ANCL cases.
Collapse
Affiliation(s)
- Ivana Jedličková
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Maxime Cadieux-Dion
- Centre Hospitalier de L´Universite de Montréal, Montréal, QC, Canada
- Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO, USA
| | - Anna Přistoupilová
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Viktor Stránecký
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Hana Hartmannová
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Kateřina Hodaňová
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Veronika Barešová
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Helena Hůlková
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Institute of Pathology, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic
| | - Jakub Sikora
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Institute of Pathology, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic
| | - Lenka Nosková
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Dita Mušálková
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Vyleťal
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jana Sovová
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Patrick Cossette
- Centre Hospitalier de L´Universite de Montréal, Montréal, QC, Canada
| | - Eva Andermann
- Montreal Neurological Hospital & Institute, McGill University, Montreal, QC, Canada
| | - Frederick Andermann
- Montreal Neurological Hospital & Institute, McGill University, Montreal, QC, Canada
| | - Stanislav Kmoch
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.
| |
Collapse
|
|
18
|
Doccini S, Morani F, Nesti C, Pezzini F, Calza G, Soliymani R, Signore G, Rocchiccioli S, Kanninen KM, Huuskonen MT, Baumann MH, Simonati A, Lalowski MM, Santorelli FM. Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction. Cell Death Discov 2020; 6:18. [PMID: 32257390 PMCID: PMC7105465 DOI: 10.1038/s41420-020-0250-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 02/27/2020] [Accepted: 03/04/2020] [Indexed: 12/20/2022] Open
Abstract
CLN5 disease is a rare form of late-infantile neuronal ceroid lipofuscinosis (NCL) caused by mutations in the CLN5 gene that encodes a protein whose primary function and physiological roles remains unresolved. Emerging lines of evidence point to mitochondrial dysfunction in the onset and progression of several forms of NCL, offering new insights into putative biomarkers and shared biological processes. In this work, we employed cellular and murine models of the disease, in an effort to clarify disease pathways associated with CLN5 depletion. A mitochondria-focused quantitative proteomics approach followed by functional validations using cell biology and immunofluorescence assays revealed an impairment of mitochondrial functions in different CLN5 KO cell models and in Cln5 - /- cerebral cortex, which well correlated with disease progression. A visible impairment of autophagy machinery coupled with alterations of key parameters of mitophagy activation process functionally linked CLN5 protein to the process of neuronal injury. The functional link between impaired cellular respiration and activation of mitophagy pathways in the human CLN5 disease condition was corroborated by translating organelle-specific proteome findings to CLN5 patients' fibroblasts. Our study highlights the involvement of CLN5 in activation of mitophagy and mitochondrial homeostasis offering new insights into alternative strategies towards the CLN5 disease treatment.
Collapse
Affiliation(s)
- Stefano Doccini
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy
| | - Federica Morani
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy
| | - Claudia Nesti
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy
| | - Francesco Pezzini
- Neurology (Child Neurology and Neuropathology), Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
| | - Giulio Calza
- Medicum, Biochemistry/Developmental Biology and HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Rabah Soliymani
- Medicum, Biochemistry/Developmental Biology and HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Giovanni Signore
- NEST, Scuola Normale Superiore, Pisa, Italy
- Fondazione Pisana per la Scienza, Pisa, Italy
| | | | - Katja M. Kanninen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Mikko T. Huuskonen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Marc H. Baumann
- Medicum, Biochemistry/Developmental Biology and HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Alessandro Simonati
- Neurology (Child Neurology and Neuropathology), Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
| | - Maciej M. Lalowski
- Medicum, Biochemistry/Developmental Biology and HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland
| | - Filippo M. Santorelli
- Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, Pisa, Italy
| |
Collapse
|
|
19
|
Imler E, Pyon JS, Kindelay S, Torvund M, Zhang YQ, Chandra SS, Zinsmaier KE. A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism. eLife 2019; 8:e46607. [PMID: 31663851 PMCID: PMC6897512 DOI: 10.7554/elife.46607] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 10/29/2019] [Indexed: 12/24/2022] Open
Abstract
The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.
Collapse
Affiliation(s)
- Elliot Imler
- Graduate Interdisciplinary Program in NeuroscienceUniversity of ArizonaTucsonUnited States
- Department of NeuroscienceUniversity of ArizonaTucsonUnited States
| | - Jin Sang Pyon
- Department of NeuroscienceUniversity of ArizonaTucsonUnited States
- Undergraduate Program in Neuroscience and Cognitive Science, Department of Molecular and Cellular BiologyUniversity of ArizonaTucsonUnited States
| | - Selina Kindelay
- Department of NeuroscienceUniversity of ArizonaTucsonUnited States
- Undergraduate Program in Neuroscience and Cognitive Science, Department of Molecular and Cellular BiologyUniversity of ArizonaTucsonUnited States
| | - Meaghan Torvund
- Graduate Interdisciplinary Program in NeuroscienceUniversity of ArizonaTucsonUnited States
- Department of NeuroscienceUniversity of ArizonaTucsonUnited States
| | - Yong-quan Zhang
- Department of NeuroscienceYale UniversityNew HavenUnited States
- Department of NeurologyYale UniversityNew HavenUnited States
| | - Sreeganga S Chandra
- Department of NeuroscienceYale UniversityNew HavenUnited States
- Department of NeurologyYale UniversityNew HavenUnited States
| | - Konrad E Zinsmaier
- Department of NeuroscienceUniversity of ArizonaTucsonUnited States
- Department of Molecular and Cellular BiologyUniversity of ArizonaTucsonUnited States
| |
Collapse
|
|
20
|
Ren XT, Wang XH, Ding CH, Shen X, Zhang H, Zhang WH, Li JW, Ren CH, Fang F. Next-Generation Sequencing Analysis Reveals Novel Pathogenic Variants in Four Chinese Siblings With Late-Infantile Neuronal Ceroid Lipofuscinosis. Front Genet 2019; 10:370. [PMID: 31105743 PMCID: PMC6494930 DOI: 10.3389/fgene.2019.00370] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 04/08/2019] [Indexed: 12/24/2022] Open
Abstract
Neuronal Ceroid Lipofuscinoses (NCLs) are progressive degenerative diseases mainly affect brain and retina. They are characterized by accumulation of autofluorescent storage material, mitochondrial ATPase subunit C, or sphingolipid activator proteins A and D in lysosomes of most cells. Heterogenous storage material in NCLs is not completely disease-specific. Most of CLN proteins and their natural substrates are not well-characterized. Studies have suggested variants of Late-Infantile NCLs (LINCLs) include the major type CLN2 and minor types CLN5, CLN6, CLN7, and CLN8. Therefore, combination of clinical and molecular analysis has become a more effective diagnosis method. We studied 4 late-infantile NCL siblings characterized by seizures, ataxia as early symptoms, followed by progressive regression in intelligence and behavior, but mutations are located in different genes. Symptoms and progression of 4 types of LINCLs are compared. Pathology of LINCLs is also discussed. We performed Nest-Generation Sequencing on these phenotypically similar families. Three novel variants c.1551+1insTGAT in TPP1, c.244G>T in CLN6, c.554-5A>G in MFSD8 were identified. Potential outcome of the mutations in structure and function of proteins are studied. In addition, we observed some common and unique clinical features of Chinese LINCL patient as compared with those of Western patients, which greatly improved our understanding of the LINCLs.
Collapse
Affiliation(s)
- Xiao-Tun Ren
- Department of Neurology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Xiao-Hui Wang
- Department of Neurology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Chang-Hong Ding
- Department of Neurology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | | | | | - Wei-Hua Zhang
- Department of Neurology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Jiu-Wei Li
- Department of Neurology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Chang-Hong Ren
- Department of Neurology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Fang Fang
- Department of Neurology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| |
Collapse
|
|
21
|
Mukherjee AB, Appu AP, Sadhukhan T, Casey S, Mondal A, Zhang Z, Bagh MB. Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses. Mol Neurodegener 2019; 14:4. [PMID: 30651094 PMCID: PMC6335712 DOI: 10.1186/s13024-018-0300-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 12/04/2018] [Indexed: 12/04/2022] Open
Abstract
Neuronal Ceroid Lipofuscinoses (NCLs), commonly known as Batten disease, constitute a group of the most prevalent neurodegenerative lysosomal storage disorders (LSDs). Mutations in at least 13 different genes (called CLNs) cause various forms of NCLs. Clinically, the NCLs manifest early impairment of vision, progressive decline in cognitive and motor functions, seizures and a shortened lifespan. At the cellular level, all NCLs show intracellular accumulation of autofluorescent material (called ceroid) and progressive neuron loss. Despite intense studies the normal physiological functions of each of the CLN genes remain poorly understood. Consequently, the development of mechanism-based therapeutic strategies remains challenging. Endolysosomal dysfunction contributes to pathogenesis of virtually all LSDs. Studies within the past decade have drastically changed the notion that the lysosomes are merely the terminal degradative organelles. The emerging new roles of the lysosome include its central role in nutrient-dependent signal transduction regulating metabolism and cellular proliferation or quiescence. In this review, we first provide a brief overview of the endolysosomal and autophagic pathways, lysosomal acidification and endosome-lysosome and autophagosome-lysosome fusions. We emphasize the importance of these processes as their dysregulation leads to pathogenesis of many LSDs including the NCLs. We also describe what is currently known about each of the 13 CLN genes and their products and how understanding the emerging new roles of the lysosome may clarify the underlying pathogenic mechanisms of the NCLs. Finally, we discuss the current and emerging therapeutic strategies for various NCLs.
Collapse
Affiliation(s)
- Anil B. Mukherjee
- Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830 USA
| | - Abhilash P. Appu
- Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830 USA
| | - Tamal Sadhukhan
- Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830 USA
| | - Sydney Casey
- Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830 USA
| | - Avisek Mondal
- Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830 USA
| | - Zhongjian Zhang
- Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830 USA
- Present address: Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, 453003 Henan China
| | - Maria B. Bagh
- Section on Developmental Genetics, Program on Endocrinology and Molecular Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830 USA
| |
Collapse
|
|
22
|
Hofmann JW, Seeley WW, Huang EJ. RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2018; 14:469-495. [PMID: 30355151 DOI: 10.1146/annurev-pathmechdis-012418-012955] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.
Collapse
Affiliation(s)
- Jeffrey W Hofmann
- Department of Pathology, University of California, San Francisco, California 94143, USA;
| | - William W Seeley
- Department of Pathology, University of California, San Francisco, California 94143, USA; .,Department of Neurology, University of California, San Francisco, California 94148, USA
| | - Eric J Huang
- Department of Pathology, University of California, San Francisco, California 94143, USA; .,Pathology Service 113B, Veterans Affairs Medical Center, San Francisco, California 94121, USA
| |
Collapse
|
|
23
|
The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol 2018; 136:1-17. [PMID: 29744576 DOI: 10.1007/s00401-018-1861-8] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 04/25/2018] [Accepted: 05/01/2018] [Indexed: 12/12/2022]
Abstract
Progranulin (PGRN), encoded by the GRN gene in humans, is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis. The clinical importance of PGRN became especially evident in 2006, when heterozygous mutations in the GRN gene, resulting in haploinsufficiency, were found to be one of the main causes of frontotemporal lobar degeneration (FTLD). FTLD is a clinically heterogenous disease that results in the progressive atrophy of the frontal and temporal lobes of the brain. Despite significant research, the exact function of PGRN and its mechanistic relationship to FTLD remain unclear. However, growing evidence suggests a role for PGRN in the lysosome-most striking being that homozygous GRN mutation leads to neuronal ceroid lipofuscinosis, a lysosomal storage disease. Since this discovery, several links between PGRN and the lysosome have been established, including the existence of two independent lysosomal trafficking pathways, intralysosomal processing of PGRN into discrete functional peptides, and direct and indirect regulation of lysosomal hydrolases. Here, we summarize the cellular functions of PGRN, its roles in the nervous system, and its link to multiple neurodegenerative diseases, with a particular focus dedicated to recent lysosome-related mechanistic developments.
Collapse
|
|
24
|
Xiao F, Fan J, Tan J, Wang XF. Clinical Reasoning: Progressive cognitive decline, cerebellar ataxia, recurrent myoclonus, and epilepsy. Neurology 2018; 90:e1827-e1831. [PMID: 29760005 DOI: 10.1212/wnl.0000000000005528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Fei Xiao
- From the Department of Neurology (F.X., J.T., X.-f.W.), The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology; and Department of Medical Laboratory Technology (J.F.), Institute of Life Sciences of Chongqing Medical University, Chongqing, China
| | - Jingchuan Fan
- From the Department of Neurology (F.X., J.T., X.-f.W.), The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology; and Department of Medical Laboratory Technology (J.F.), Institute of Life Sciences of Chongqing Medical University, Chongqing, China
| | - Jiaze Tan
- From the Department of Neurology (F.X., J.T., X.-f.W.), The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology; and Department of Medical Laboratory Technology (J.F.), Institute of Life Sciences of Chongqing Medical University, Chongqing, China
| | - Xue-Feng Wang
- From the Department of Neurology (F.X., J.T., X.-f.W.), The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology; and Department of Medical Laboratory Technology (J.F.), Institute of Life Sciences of Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
25
|
Studniarczyk D, Needham EL, Mitchison HM, Farrant M, Cull-Candy SG. Altered Cerebellar Short-Term Plasticity but No Change in Postsynaptic AMPA-Type Glutamate Receptors in a Mouse Model of Juvenile Batten Disease. eNeuro 2018; 5:ENEURO.0387-17.2018. [PMID: 29780879 PMCID: PMC5956745 DOI: 10.1523/eneuro.0387-17.2018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 03/22/2018] [Accepted: 03/27/2018] [Indexed: 12/28/2022] Open
Abstract
Juvenile Batten disease is the most common progressive neurodegenerative disorder of childhood. It is associated with mutations in the CLN3 gene, causing loss of function of CLN3 protein and degeneration of cerebellar and retinal neurons. It has been proposed that changes in granule cell AMPA-type glutamate receptors (AMPARs) contribute to the cerebellar dysfunction. In this study, we compared AMPAR properties and synaptic transmission in cerebellar granule cells from wild-type and Cln3 knock-out mice. In Cln3Δex1-6 cells, the amplitude of AMPA-evoked whole-cell currents was unchanged. Similarly, we found no change in the amplitude, kinetics, or rectification of synaptic currents evoked by individual quanta, or in their underlying single-channel conductance. We found no change in cerebellar expression of GluA2 or GluA4 protein. By contrast, we observed a reduced number of quantal events following mossy-fiber stimulation in Sr2+, altered short-term plasticity in conditions of reduced extracellular Ca2+, and reduced mossy fiber vesicle number. Thus, while our results suggest early presynaptic changes in the Cln3Δex1-6 mouse model of juvenile Batten disease, they reveal no evidence for altered postsynaptic AMPARs.
Collapse
Affiliation(s)
- Dorota Studniarczyk
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom
| | - Elizabeth L. Needham
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom
| | - Hannah M. Mitchison
- UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, United Kingdom
| | - Mark Farrant
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom
| | - Stuart G. Cull-Candy
- Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom
| |
Collapse
|
|
26
|
Gao Z, Xie H, Jiang Q, Wu N, Chen X, Chen Q. Identification of two novel null variants in CLN8 by targeted next-generation sequencing: first report of a Chinese patient with neuronal ceroid lipofuscinosis due to CLN8 variants. BMC MEDICAL GENETICS 2018; 19:21. [PMID: 29422019 PMCID: PMC5806251 DOI: 10.1186/s12881-018-0535-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 01/24/2018] [Indexed: 01/17/2023]
Abstract
BACKGROUND Neuronal ceroid lipofuscinoses (NCLs) are one of the most frequent childhood-onset neurodegenerative pathologies characterized by seizures, progressive cognitive decline, motor impairment and loss of vision. For the past two decades, more than 430 variants in 13 candidate genes have been identified in the affected patients. Most of the variants were almost exclusively reported in Western patients, and very little clinical and genetic information was available for Chinese patients. CASE PRESENTATION We report a Chinese boy whose clinical phenotypes were suspected to be NCL, including intractable epilepsy, cognitive and motor decline and progressive vision loss. Using targeted next-generation sequencing, two novel null variants in CLN8 (c.298C > T, p.Gln100Ter; c.551G > A, p.Trp184Ter) were detected in this patient in trans model. These two variants were interpreted as pathogenic according to the variant guidelines of the American College of Medical Genetics and Genomics. CONCLUSIONS This is the first case report of NCL due to CLN8 variants in China. Our findings expand the variant diversity of CLN8 and demonstrate the tremendous diagnosis value of targeted next-generation sequencing for pediatric NCLs.
Collapse
Affiliation(s)
- Zhijie Gao
- Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics, No. 2, Yabao Road, Chaoyang District, Beijing, 100020, China
| | - Hua Xie
- Department of Medical Genetics, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Qian Jiang
- Department of Medical Genetics, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Nan Wu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, 100020, China
| | - Xiaoli Chen
- Department of Medical Genetics, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China.
| | - Qian Chen
- Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics, No. 2, Yabao Road, Chaoyang District, Beijing, 100020, China.
| |
Collapse
|
|
27
|
Wang C, Xu H, Yuan Y, Lian Y, Xie N, Ming L. Novel compound heterozygous mutations causing Kufs disease type B. Int J Neurosci 2017; 128:573-576. [PMID: 29120254 DOI: 10.1080/00207454.2017.1403439] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Kufs disease type B (also termed CLN13), an adult-onset form of neuronal ceroid lipofuscinosis (NCL), is genetically heterogeneous and challenging to diagnose. Recently, mutations in cathepsin-F have been identified as the causative gene for autosomal recessive Kufs disease type B. RESULTS Here, we report a sporadic case of Kufs disease type B with novel compound heterozygous mutations, a novel missense mutation c.977G>T (p.C326F) and a novel nonsense mutation c.416C>A (p.S139X), in the cathepsin-F gene. The magnetic resonance imaging findings were consistent with those demonstrated in adult neuronal ceroid lipofuscinosis: diffuse cortical atrophy, mild hyperintensity and reduction of the deep white matter on T2-weighted images. A skin biopsy was negative for abnormalities. CONCLUSIONS Altogether, our findings broaden the mutation database in relation to the neuronal ceroid lipofuscinosis, and the clinical diagnosis of Kufs disease type B was confirmed.
Collapse
Affiliation(s)
- Cui Wang
- a Department of Clinical Laboratory , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China.,b Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Hongliang Xu
- c Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Yun Yuan
- d Department of Neurology , Peking University First Hospital , Beijing , China
| | - Yajun Lian
- c Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Nanchang Xie
- c Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Liang Ming
- a Department of Clinical Laboratory , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China.,b Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| |
Collapse
|
|
28
|
Cudjoe EK, Saleh T, Hawkridge AM, Gewirtz DA. Proteomics Insights into Autophagy. Proteomics 2017; 17. [DOI: 10.1002/pmic.201700022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 08/25/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Emmanuel K. Cudjoe
- Department of Pharmacotherapy & Outcomes Science; Virginia Commonwealth University; Richmond VA
| | - Tareq Saleh
- Department of Pharmacology & Toxicology; Virginia Commonwealth University; Richmond VA
| | - Adam M. Hawkridge
- Department of Pharmacotherapy & Outcomes Science; Virginia Commonwealth University; Richmond VA
- Department of Pharmaceutics; Virginia Commonwealth University; Richmond VA
| | - David A. Gewirtz
- Department of Pharmacology & Toxicology; Virginia Commonwealth University; Richmond VA
- Massey Cancer Center; Virginia Commonwealth University; Richmond VA
| |
Collapse
|
|
29
|
Nelvagal HR, Cooper JD. Translating preclinical models of neuronal ceroid lipofuscinosis: progress and prospects. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1360182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Hemanth R. Nelvagal
- Pediatric Storage Disorders Laboratory, Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, UCLA, Torrance, CA, USA
| | - Jonathan D. Cooper
- Pediatric Storage Disorders Laboratory, Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, UCLA, Torrance, CA, USA
| |
Collapse
|
|
30
|
Zhou X, Sullivan PM, Sun L, Hu F. The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C. J Neurochem 2017. [PMID: 28640985 DOI: 10.1111/jnc.14110] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
The frontotemporal lobar degeneration (FTLD) protein progranulin (PGRN) is essential for proper lysosomal function. PGRN localizes in the lysosomal compartment within the cell. Prosaposin (PSAP), the precursor of lysosomal saposin activators (saposin A, B, C, D), physically interacts with PGRN. Previously, we have shown that PGRN and PSAP facilitate each other's lysosomal trafficking. Here, we report that the interaction between PSAP and PGRN requires the linker region of saposin B and C (BC linker). PSAP protein with the BC linker mutated, fails to interact with PGRN and deliver PGRN to lysosomes in the biosynthetic and endocytic pathways. On the other hand, PGRN interacts with PSAP through multiple granulin motifs. Granulin D and E bind to PSAP with similar affinity as full-length PGRN. Read the Editorial Comment for this article on page 154.
Collapse
Affiliation(s)
- Xiaolai Zhou
- Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA
| | - Peter M Sullivan
- Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA
| | - Lirong Sun
- Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA
| | - Fenghua Hu
- Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York, USA
| |
Collapse
|
|
31
|
Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis. Sci Rep 2017; 7:6332. [PMID: 28740222 PMCID: PMC5524943 DOI: 10.1038/s41598-017-06710-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 06/15/2017] [Indexed: 01/14/2023] Open
Abstract
Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities. AFSM accumulation correlates with CSPα aggregation and both are susceptible to pharmacological modulation of ALP function. In addition, we demonstrate that endogenous CSPα is present in the lysosome-enriched fractions and co-localizes with lysosome markers in soma, neurites and synaptic boutons. Overexpression of CSPα wild-type (WT) decreases lysotracker signal, secreted lysosomal enzymes and SNAP23-mediated lysosome exocytosis. CSPα WT, mutant and aggregated CSPα are degraded mainly by the ALP but this disease-causing mutation exhibits a faster rate of degradation. Co-expression of both WT and mutant CSPα cause a block in the fusion of autophagosomes/lysosomes. Our data suggest that aggregation-dependent perturbation of ALP function is a relevant pathogenic mechanism for AD-ANCL and supports the use of AFSM or CSPα aggregation as biomarkers for drug screening purposes.
Collapse
|
|
32
|
Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations. Nat Commun 2017; 8:15277. [PMID: 28541286 PMCID: PMC5477518 DOI: 10.1038/ncomms15277] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 03/15/2017] [Indexed: 01/01/2023] Open
Abstract
Haploinsufficiency of progranulin (PGRN) due to mutations in the granulin (GRN) gene causes frontotemporal lobar degeneration (FTLD), and complete loss of PGRN leads to a lysosomal storage disorder, neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests that PGRN is essential for proper lysosomal function, but the precise mechanisms involved are not known. Here, we show that PGRN facilitates neuronal uptake and lysosomal delivery of prosaposin (PSAP), the precursor of saposin peptides that are essential for lysosomal glycosphingolipid degradation. We found reduced levels of PSAP in neurons both in mice deficient in PGRN and in human samples from FTLD patients due to GRN mutations. Furthermore, mice with reduced PSAP expression demonstrated FTLD-like pathology and behavioural changes. Thus, our data demonstrate a role of PGRN in PSAP lysosomal trafficking and suggest that impaired lysosomal trafficking of PSAP is an underlying disease mechanism for NCL and FTLD due to GRN mutations. Mutations in the granulin gene are associated with frontotemporal lobe dementia (FTLD) and a lysosomal storage disease. The authors show that reduced progranulin levels leads to impaired neuronal uptake and lysosomal delivery of prosaposin, and that decreased prosaposin expression in mice leads to FTLD-like behaviour.
Collapse
|
|
33
|
Elevated TMEM106B levels exaggerate lipofuscin accumulation and lysosomal dysfunction in aged mice with progranulin deficiency. Acta Neuropathol Commun 2017; 5:9. [PMID: 28126008 PMCID: PMC5270347 DOI: 10.1186/s40478-017-0412-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 01/14/2017] [Indexed: 12/12/2022] Open
Abstract
Mutations resulting in haploinsufficiency of progranulin (PGRN) cause frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), a devastating neurodegenerative disease. Accumulating evidence suggest a crucial role of progranulin in maintaining proper lysosomal function during aging. TMEM106B has been identified as a risk factor for frontotemporal lobar degeneration with progranulin mutations and elevated mRNA and protein levels of TMEM106B are associated with increased risk for frontotemporal lobar degeneration. Increased levels of TMEM106B alter lysosomal morphology and interfere with lysosomal degradation. However, how progranulin and TMEM106B interact to regulate lysosomal function and frontotemporal lobar degeneration (FTLD) disease progression is still unclear. Here we report that progranulin deficiency leads to increased TMEM106B protein levels in the mouse cortex with aging. To mimic elevated levels of TMEM106B in frontotemporal lobar degeneration (FTLD) cases, we generated transgenic mice expressing TMEM106B under the neuronal specific promoter, CamKII. Surprisingly, we found that the total protein levels of TMEM106B are not altered despite the expression of the TMEM106B transgene at mRNA and protein levels, suggesting a tight regulation of TMEM106B protein levels in the mouse brain. However, progranulin deficiency results in accumulation of TMEM106B protein from the transgene expression during aging, which is accompanied by exaggerated lysosomal abnormalities and increased lipofuscin accumulation. In summary, our mouse model nicely recapitulates the interaction between progranulin and TMEM106B in human patients and supports a critical role of lysosomal dysfunction in the frontotemporal lobar degeneration (FTLD) disease progression.
Collapse
|
|
34
|
Moen MN, Fjær R, Hamdani EH, Laerdahl JK, Menchini RJ, Vigeland MD, Sheng Y, Undlien DE, Hassel B, Salih MA, El Khashab HY, Selmer KK, Chaudhry FA. Pathogenic variants in KCTD7 perturb neuronal K+ fluxes and glutamine transport. Brain 2016; 139:3109-3120. [PMID: 27742667 DOI: 10.1093/brain/aww244] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 06/11/2016] [Accepted: 08/17/2016] [Indexed: 12/11/2022] Open
Abstract
Progressive myoclonus epilepsy is a heterogeneous group of disorders characterized by myoclonic and tonic-clonic seizures, ataxia and cognitive decline. We here present two affected brothers. At 9 months of age the elder brother developed ataxia and myoclonic jerks. In his second year he lost the ability to walk and talk, and he developed drug-resistant progressive myoclonus epilepsy. The cerebrospinal fluid level of glutamate was decreased while glutamine was increased. His younger brother manifested similar symptoms from 6 months of age. By exome sequencing of the proband we identified a novel homozygous frameshift variant in the potassium channel tetramerization domain 7 (KCTD7) gene (NM_153033.1:c.696delT: p.F232fs), which results in a truncated protein. The identified F232fs variant is inherited in an autosomal recessive manner, and the healthy consanguineous parents carry the variant in a heterozygous state. Bioinformatic analyses and structure modelling showed that KCTD7 is a highly conserved protein, structurally similar to KCTD5 and several voltage-gated potassium channels, and that it may form homo- or heteromultimers. By heterologous expression in Xenopus laevis oocytes, we demonstrate that wild-type KCTD7 hyperpolarizes cells in a K+ dependent manner and regulates activity of the neuronal glutamine transporter SAT2 (Slc38a2), while the F232fs variant impairs K+ fluxes and obliterates SAT2-dependent glutamine transport. Characterization of four additional disease-causing variants (R94W, R184C, N273I, Y276C) bolster these results and reveal the molecular mechanisms involved in the pathophysiology of KCTD7-related progressive myoclonus epilepsy. Thus, our data demonstrate that KCTD7 has an impact on K+ fluxes, neurotransmitter synthesis and neuronal function, and that malfunction of the encoded protein may lead to progressive myoclonus epilepsy.
Collapse
Affiliation(s)
- Marivi Nabong Moen
- 1 The Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway
| | - Roar Fjær
- 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway
| | - El Hassan Hamdani
- 1 The Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway.,3 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Jon K Laerdahl
- 4 Department of Microbiology, Oslo University Hospital, Oslo, Norway.,5 Bioinformatics Core Facility, Department of Informatics, University of Oslo, Oslo, Norway
| | - Robin Johansen Menchini
- 1 The Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway
| | - Magnus Dehli Vigeland
- 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway
| | - Ying Sheng
- 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway
| | - Dag Erik Undlien
- 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway
| | - Bjørnar Hassel
- 6 Department of Complex Neurology and Neurohabilitation, Oslo University Hospital, Oslo, Norway
| | - Mustafa A Salih
- 7 Division of Paediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Heba Y El Khashab
- 7 Division of Paediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,8 Department of Paediatrics, Ain Shams University, Cairo, Egypt
| | - Kaja Kristine Selmer
- 2 Department of Medical Genetics, Oslo University Hospital and University of Oslo, Norway.,9 National Centre for Rare Epilepsy-related Disorders, Oslo University Hospital, Oslo, Norway
| | - Farrukh Abbas Chaudhry
- 1 The Institute of Basic Medical Sciences, Department of Molecular Medicine, University of Oslo, Oslo, Norway .,3 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| |
Collapse
|
|
35
|
Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell 2016; 165:921-35. [PMID: 27114033 DOI: 10.1016/j.cell.2016.04.001] [Citation(s) in RCA: 541] [Impact Index Per Article: 60.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 03/10/2016] [Accepted: 03/31/2016] [Indexed: 11/20/2022]
Abstract
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.
Collapse
|
|
36
|
Onyenwoke RU, Brenman JE. Lysosomal Storage Diseases-Regulating Neurodegeneration. J Exp Neurosci 2016; 9:81-91. [PMID: 27081317 PMCID: PMC4822725 DOI: 10.4137/jen.s25475] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 11/11/2015] [Accepted: 11/16/2015] [Indexed: 12/19/2022] Open
Abstract
Autophagy is a complex pathway regulated by numerous signaling events that recycles macromolecules and can be perturbed in lysosomal storage diseases (LSDs). The concept of LSDs, which are characterized by aberrant, excessive storage of cellular material in lysosomes, developed following the discovery of an enzyme deficiency as the cause of Pompe disease in 1963. Great strides have since been made in better understanding the biology of LSDs. Defective lysosomal storage typically occurs in many cell types, but the nervous system, including the central nervous system and peripheral nervous system, is particularly vulnerable to LSDs, being affected in two-thirds of LSDs. This review provides a summary of some of the better characterized LSDs and the pathways affected in these disorders.
Collapse
Affiliation(s)
- Rob U Onyenwoke
- Department of Pharmaceutical Science, Biomanufacturing Research Institute and Technology Enterprise (BRITE), North Carolina Central University, Durham, NC, USA
| | - Jay E Brenman
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| |
Collapse
|
|
37
|
Henderson MX, Wirak GS, Zhang YQ, Dai F, Ginsberg SD, Dolzhanskaya N, Staropoli JF, Nijssen PCG, Lam TT, Roth AF, Davis NG, Dawson G, Velinov M, Chandra SS. Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. Acta Neuropathol 2016; 131:621-37. [PMID: 26659577 DOI: 10.1007/s00401-015-1512-2] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 11/17/2015] [Accepted: 11/19/2015] [Indexed: 01/09/2023]
Abstract
Neuronal ceroid lipofuscinoses (NCL) are a group of inherited neurodegenerative disorders with lysosomal pathology (CLN1-14). Recently, mutations in the DNAJC5/CLN4 gene, which encodes the presynaptic co-chaperone CSPα were shown to cause autosomal-dominant NCL. Although 14 NCL genes have been identified, it is unknown if they act in common disease pathways. Here we show that two disease-associated proteins, CSPα and the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1/CLN1) are biochemically linked. We find that in DNAJC5/CLN4 patient brains, PPT1 is massively increased and mis-localized. Surprisingly, the specific enzymatic activity of PPT1 is dramatically reduced. Notably, we demonstrate that CSPα is depalmitoylated by PPT1 and hence its substrate. To determine the consequences of PPT1 accumulation, we compared the palmitomes from control and DNAJC5/CLN4 patient brains by quantitative proteomics. We discovered global changes in protein palmitoylation, mainly involving lysosomal and synaptic proteins. Our findings establish a functional link between two forms of NCL and serve as a springboard for investigations of NCL disease pathways.
Collapse
Affiliation(s)
- Michael X Henderson
- Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA
- Department of Neurology, Yale University, New Haven, CT, USA
- Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA
| | - Gregory S Wirak
- Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA
- Department of Neurology, Yale University, New Haven, CT, USA
| | - Yong-Quan Zhang
- Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA
- Department of Neurology, Yale University, New Haven, CT, USA
| | - Feng Dai
- Yale Center for Analytical Services, New Haven, CT, USA
| | - Stephen D Ginsberg
- Nathan Kline Institute, Orangeburg, NY, USA
- Departments of Psychiatry and Physiology and Neuroscience, New York University Langone Medical Center, New York, NY, USA
| | - Natalia Dolzhanskaya
- Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| | - John F Staropoli
- Department of Neurology, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
- Biogen Idec, Cambridge, MA, 02142, USA
| | - Peter C G Nijssen
- Department of Neurology, St. Elisabeth Hospital, 5022 GC, Tilburg, Netherlands
| | - TuKiet T Lam
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
| | - Amy F Roth
- Department of Pharmacology, Wayne State University, Detroit, MI, USA
| | - Nicholas G Davis
- Department of Pharmacology, Wayne State University, Detroit, MI, USA
| | - Glyn Dawson
- Department of Pediatrics, University of Chicago, Chicago, IL, USA
| | - Milen Velinov
- Department of Pediatrics, Albert Einstein College of Medicine, New York, NY, USA
- Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| | - Sreeganga S Chandra
- Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, New Haven, CT, USA.
- Department of Neurology, Yale University, New Haven, CT, USA.
- Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA.
- Department of Molecular Cell and Developmental Biology, Yale University, New Haven, CT, USA.
| |
Collapse
|
|
38
|
Intracerebroventricular gene therapy that delays neurological disease progression is associated with selective preservation of retinal ganglion cells in a canine model of CLN2 disease. Exp Eye Res 2016; 146:276-282. [PMID: 27039708 PMCID: PMC4957944 DOI: 10.1016/j.exer.2016.03.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 03/25/2016] [Accepted: 03/28/2016] [Indexed: 12/13/2022]
Abstract
CLN2 disease is one of a group of lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs). The disease results from mutations in the TPP1 gene that cause an insufficiency or complete lack of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). TPP1 is involved in lysosomal protein degradation, and lack of this enzyme results in the accumulation of protein-rich autofluorescent lysosomal storage bodies in numerous cell types including neurons throughout the central nervous system and the retina. CLN2 disease is characterized primarily by progressive loss of neurological functions and vision as well as generalized neurodegeneration and retinal degeneration. In children the progressive loss of neurological functions typically results in death by the early teenage years. A Dachshund model of CLN2 disease with a null mutation in TPP1 closely recapitulates the human disorder with a progression from disease onset at approximately 4 months of age to end-stage at 10-11 months. Delivery of functional TPP1 to the cerebrospinal fluid (CSF), either by periodic infusion of the recombinant protein or by a single administration of a TPP1 gene therapy vector to the CSF, significantly delays the onset and progression of neurological signs and prolongs life span but does not prevent the loss of vision or modest retinal degeneration that occurs by 11 months of age. In this study we found that in dogs that received the CSF gene therapy treatment, the degeneration of the retina and loss of retinal function continued to progress during the prolonged life spans of the treated dogs. Eventually the normal cell layers of the retina almost completely disappeared. An exception was the ganglion cell layer. In affected dogs that received TPP1 gene therapy to the CSF and survived an average of 80 weeks, ganglion cell axons were present in numbers comparable to those of normal Dachshunds of similar age. The selective preservation of the retinal ganglion cells suggests that while TPP1 protein delivered via the CSF may protect these cells, preservation of the remainder of the retina will require delivery of normal TPP1 more directly to the retina, probably via the vitreous body.
Collapse
|
|
39
|
Ouseph MM, Kleinman ME, Wang QJ. Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease). Ann N Y Acad Sci 2016; 1371:55-67. [PMID: 26748992 DOI: 10.1111/nyas.12990] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Juvenile neuronal ceroid lipofuscinosis (JNCL; also known as CLN3 disease) is a devastating neurodegenerative lysosomal storage disorder and the most common form of Batten disease. Progressive visual and neurological symptoms lead to mortality in patients by the third decade. Although ceroid-lipofuscinosis, neuronal 3 (CLN3) has been identified as the sole disease gene, the biochemical and cellular bases of JNCL and the functions of CLN3 are yet to be fully understood. As severe ocular pathologies manifest early in disease progression, the retina is an ideal tissue to study in the efforts to unravel disease etiology and design therapeutics. There are significant discrepancies in the ocular phenotypes between human JNCL and existing murine models, impeding investigations on the sequence of events occurring during the progression of vision impairment. This review focuses on current understanding of vision loss in JNCL and discusses future research directions toward molecular dissection of the pathogenesis of the disease and associated vision problems in order to ultimately improve the quality of patient life and cure the disease.
Collapse
Affiliation(s)
| | | | - Qing Jun Wang
- Department of Molecular and Cellular Biochemistry.,Department of Toxicology and Cancer Biology.,Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| |
Collapse
|
|
40
|
Wavre-Shapton ST, Calvi AA, Turmaine M, Seabra MC, Cutler DF, Futter CE, Mitchison HM. Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium of Cln3Δex1-6 mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease). Hum Mol Genet 2015; 24:7060-74. [PMID: 26450516 PMCID: PMC4654058 DOI: 10.1093/hmg/ddv406] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 09/22/2015] [Indexed: 12/21/2022] Open
Abstract
Retinal degeneration and visual impairment are the first signs of juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations, followed by inevitable progression to blindness. We investigated retinal degeneration in Cln3(Δex1-6) null mice, revealing classic 'fingerprint' lysosomal storage in the retinal pigment epithelium (RPE), replicating the human disease. The lysosomes contain mitochondrial F0-ATP synthase subunit c along with undigested membranes, indicating a reduced degradative capacity. Mature autophagosomes and basal phagolysosomes, the terminal degradative compartments of autophagy and phagocytosis, are also increased in Cln3(Δex1) (-6) RPE, reflecting disruption to these key pathways that underpin the daily phagocytic turnover of photoreceptor outer segments (POS) required for maintenance of vision. The accumulated autophagosomes have post-lysosome fusion morphology, with undigested internal contents visible, while accumulated phagosomes are frequently docked to cathepsin D-positive lysosomes, without mixing of phagosomal and lysosomal contents. This suggests lysosome-processing defects affect both autophagy and phagocytosis, supported by evidence that phagosomes induced in Cln3(Δex1) (-) (6)-derived mouse embryonic fibroblasts have visibly disorganized membranes, unprocessed internal vesicles and membrane contents, in addition to reduced LAMP1 membrane recruitment. We propose that defective lysosomes in Cln3(Δex1) (-) (6) RPE have a reduced degradative capacity that impairs the final steps of the intimately connected autophagic and phagocytic pathways that are responsible for degradation of POS. A build-up of degradative organellar by-products and decreased recycling of cellular materials is likely to disrupt processes vital to maintenance of vision by the RPE.
Collapse
Affiliation(s)
- Silène T Wavre-Shapton
- UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK, Molecular Medicine, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK
| | - Alessandra A Calvi
- Nuclear Dynamics and Architecture, Institute of Medical Biology, Singapore 138648, Singapore
| | - Mark Turmaine
- Faculty of Life Sciences, Division of Biosciences and
| | - Miguel C Seabra
- Molecular Medicine, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK
| | - Daniel F Cutler
- Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK and MRC Cell Biology Unit, MRC Laboratory for Molecular Cell Biology, London, UK
| | - Clare E Futter
- UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK,
| | - Hannah M Mitchison
- Genetics and Genomic Medicine Programme and Birth Defects Research Centre, Institute of Child Health, University College London, London WC1N 1EH, UK,
| |
Collapse
|
|
41
|
Benitez BA, Cairns NJ, Schmidt RE, Morris JC, Norton JB, Cruchaga C, Sands MS. Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss. Acta Neuropathol Commun 2015; 3:73. [PMID: 26610600 PMCID: PMC4660676 DOI: 10.1186/s40478-015-0256-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 11/13/2015] [Indexed: 01/18/2023] Open
Abstract
Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the DNAJC5 gene. DNAJC5 encodes Cysteine String Protein-alpha (CSPα), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on the intracellular accumulation of ceroid material. Here, we report for the first time the pathological findings of a patient in a clinically early stage of disease, which exhibits the typical neuronal intracellular ceroid accumulation and incipient neuroinflammation but no signs of brain atrophy, neurodegeneration or massive synaptic loss. Interestingly, we found minimal or no apparent reductions in CSPα or synaptophysin in the neuropil. In contrast, brain homogenates from terminal AD-ANCL patients exhibit significant reductions in SNARE-complex forming presynaptic protein levels, including a significant reduction in CSPα and SNAP-25. Frozen samples for the biochemical analyses of synaptic proteins were not available for the early stage AD-ANLC patient. These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of CSPα mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction.
Collapse
|
|
42
|
Peng S, Xu J, Pelkey KA, Chandra G, Zhang Z, Bagh MB, Yuan X, Wu LG, McBain CJ, Mukherjee AB. Suppression of agrin-22 production and synaptic dysfunction in Cln1 (-/-) mice. Ann Clin Transl Neurol 2015; 2:1085-104. [PMID: 26734660 PMCID: PMC4693586 DOI: 10.1002/acn3.261] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 09/10/2015] [Accepted: 10/02/2015] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE Oxidative stress in the brain is highly prevalent in many neurodegenerative disorders including lysosomal storage disorders, in which neurodegeneration is a devastating manifestation. Despite intense studies, a precise mechanism linking oxidative stress to neuropathology in specific neurodegenerative diseases remains largely unclear. METHODS Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease caused by mutations in the ceroid lipofuscinosis neuronal-1 (CLN1) gene encoding palmitoyl-protein thioesterase-1. Previously, we reported that in the brain of Cln1 (-/-) mice, which mimic INCL, and in postmortem brain tissues from INCL patients, increased oxidative stress is readily detectable. We used molecular, biochemical, immunohistological, and electrophysiological analyses of brain tissues of Cln1 (-/-) mice to study the role(s) of oxidative stress in mediating neuropathology. RESULTS Our results show that in Cln1 (-/-) mice oxidative stress in the brain via upregulation of the transcription factor, CCAAT/enhancer-binding protein-δ, stimulated expression of serpina1, which is an inhibitor of a serine protease, neurotrypsin. Moreover, in the Cln1 (-/-) mice, suppression of neurotrypsin activity by serpina1 inhibited the cleavage of agrin (a large proteoglycan), which substantially reduced the production of agrin-22, essential for synaptic homeostasis. Direct whole-cell recordings at the nerve terminals of Cln1 (-/-) mice showed inhibition of Ca(2+) currents attesting to synaptic dysfunction. Treatment of these mice with a thioesterase-mimetic small molecule, N-tert (Butyl) hydroxylamine (NtBuHA), increased agrin-22 levels. INTERPRETATION Our findings provide insight into a novel pathway linking oxidative stress with synaptic pathology in Cln1 (-/-) mice and suggest that NtBuHA, which increased agrin-22 levels, may ameliorate synaptic dysfunction in this devastating neurodegenerative disease.
Collapse
Affiliation(s)
- Shiyong Peng
- Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830
| | - Jianhua Xu
- Synaptic Transmission Section (HNQ23-R) National Institute of Neurological Disorders and Stroke NIH Bethesda Maryland 20892
| | - Kenneth A Pelkey
- The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715
| | - Goutam Chandra
- Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830
| | - Zhongjian Zhang
- Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830
| | - Maria B Bagh
- Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830
| | - Xiaoqing Yuan
- The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715
| | - Ling-Gang Wu
- Synaptic Transmission Section (HNQ23-R) National Institute of Neurological Disorders and Stroke NIH Bethesda Maryland 20892
| | - Chris J McBain
- The Program in Developmental Neuroscience Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-3715
| | - Anil B Mukherjee
- Section on Developmental Genetics Program on Developmental Endocrinology and Genetics Eunice Kennedy-Shriver National Institute of Child Health and Human Development NIH Bethesda Maryland 20892-1830
| |
Collapse
|
|
43
|
Human NCL Neuropathology. Biochim Biophys Acta Mol Basis Dis 2015; 1852:2262-6. [DOI: 10.1016/j.bbadis.2015.05.007] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 05/07/2015] [Accepted: 05/11/2015] [Indexed: 11/21/2022]
|
|
44
|
Rama Rao KV, Kielian T. Neuron-astrocyte interactions in neurodegenerative diseases: Role of neuroinflammation. ACTA ACUST UNITED AC 2015; 6:245-263. [PMID: 26543505 DOI: 10.1111/cen3.12237] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Selective neuron loss in discrete brain regions is a hallmark of various neurodegenerative disorders, although the mechanisms responsible for this regional vulnerability of neurons remain largely unknown. Earlier studies attributed neuron dysfunction and eventual loss during neurodegenerative diseases as exclusively cell autonomous. Although cell-intrinsic factors are one critical aspect in dictating neuron death, recent evidence also supports the involvement of other central nervous system cell types in propagating non-cell autonomous neuronal injury during neurodegenerative diseases. One such example is astrocytes, which support neuronal and synaptic function, but can also contribute to neuroinflammatory processes through robust chemokine secretion. Indeed, aberrations in astrocyte function have been shown to negatively impact neuronal integrity in several neurological diseases. The present review focuses on neuroinflammatory paradigms influenced by neuron-astrocyte cross-talk in the context of select neurodegenerative diseases.
Collapse
Affiliation(s)
- Kakulavarapu V Rama Rao
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Tammy Kielian
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| |
Collapse
|
|
45
|
Baker EH, Levin SW, Zhang Z, Mukherjee AB. Evaluation of disease progression in INCL by MR spectroscopy. Ann Clin Transl Neurol 2015; 2:797-809. [PMID: 26339674 PMCID: PMC4554441 DOI: 10.1002/acn3.222] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 05/13/2015] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS). METHODS A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients. RESULTS In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently. INTERPRETATION Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.
Collapse
Affiliation(s)
- Eva H Baker
- Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health Bethesda, Maryland, USA, 20892
| | - Sondra W Levin
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Bethesda, Maryland, USA, 20892 ; Department of Pediatrics, Walter Reed National Military Medical Center Bethesda, Maryland, USA, 20889-5600
| | - Zhongjian Zhang
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Bethesda, Maryland, USA, 20892
| | - Anil B Mukherjee
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Bethesda, Maryland, USA, 20892
| |
Collapse
|
|
46
|
Meyer S, Yilmaz U, Kim YJ, Steinfeld R, Meyberg-Solomayer G, Oehl-Jaschkowitz B, Tzschach A, Gortner L, Igel J, Schofer O. Congenital CLN disease in two siblings. Wien Med Wochenschr 2015; 165:210-3. [PMID: 26059544 DOI: 10.1007/s10354-015-0359-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 05/04/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND Neuronal ceroid lipofuscinoses (NCL) is characterized by a combination of retinopathy, dementia, and epilepsy. As a group, they encompass ten distinct biological and clinical entities and are the most common type of childhood neurodegenerative disease. PATIENTS AND METHODS Case reports. RESULTS We demonstrate the clinical course of two neonates (brother and sister) with infantile neuronal ceroid lipofuscinoses (NCL) (CLN 10 disease) presenting with intractable seizures and respiratory insufficiency immediately after birth. Characteristic clinical, radiological and pathological findings of this form of NCL are presented. CONCLUSIONS We conclude that the diagnosis of CLN10 should be kept in mind as a differential diagnosis in newborns presenting with respiratory insufficiency and severe epilepsy that is largely refractory to anti-epileptic drugs (AED) treatment. Because of the severity of CLN10 disease and futility of treatment, important ethical issues arise when caring for children with this clinical entity.
Collapse
Affiliation(s)
- Sascha Meyer
- Department of Pediatrics and Neonatology (Neonatal Intensive Care Unit), University Children´s Hospital of Saarland/Saarland University Hospitals, Building 9, 66421, Homburg, Germany,
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Gilliam D, Kolicheski A, Johnson GS, Mhlanga-Mutangadura T, Taylor JF, Schnabel RD, Katz ML. Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5. Mol Genet Metab 2015; 115:101-9. [PMID: 25934231 DOI: 10.1016/j.ymgme.2015.04.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/14/2015] [Accepted: 04/14/2015] [Indexed: 11/20/2022]
Abstract
We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletion-allele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever, thereby preserving an opportunity for us or others to establish a colony of CLN5-deficient dogs.
Collapse
Affiliation(s)
- D Gilliam
- Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO, USA.
| | - A Kolicheski
- Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO, USA.
| | - G S Johnson
- Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO, USA.
| | - T Mhlanga-Mutangadura
- Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO, USA.
| | - J F Taylor
- Division of Animal Science, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, MO, USA.
| | - R D Schnabel
- Division of Animal Science, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, MO, USA.
| | - M L Katz
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO, USA.
| |
Collapse
|
|
48
|
Rama Rao KV, Kielian T. Astrocytes and lysosomal storage diseases. Neuroscience 2015; 323:195-206. [PMID: 26037807 DOI: 10.1016/j.neuroscience.2015.05.061] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 05/21/2015] [Accepted: 05/22/2015] [Indexed: 12/19/2022]
Abstract
Lysosomal storage diseases (LSDs) encompass a wide range of disorders characterized by inborn errors of lysosomal function. The majority of LSDs result from genetic defects in lysosomal enzymes, although some arise from mutations in lysosomal proteins that lack known enzymatic activity. Neuropathological abnormalities are a feature of several LSDs and when severe, represent an important determinant in disease outcome. Glial dysfunction, particularly in astrocytes, is also observed in numerous LSDs and has been suggested to impact neurodegeneration. This review will discuss the potential role of astrocytes in LSDs and highlight the possibility of targeting glia as a beneficial strategy to counteract the neuropathology associated with LSDs.
Collapse
Affiliation(s)
- K V Rama Rao
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - T Kielian
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States.
| |
Collapse
|
|
49
|
Cell biology of the NCL proteins: What they do and don't do. Biochim Biophys Acta Mol Basis Dis 2015; 1852:2242-55. [PMID: 25962910 DOI: 10.1016/j.bbadis.2015.04.027] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 04/23/2015] [Accepted: 04/24/2015] [Indexed: 02/06/2023]
Abstract
The fatal, primarily childhood neurodegenerative disorders, neuronal ceroid lipofuscinoses (NCLs), are currently associated with mutations in 13 genes. The protein products of these genes (CLN1 to CLN14) differ in their function and their intracellular localization. NCL-associated proteins have been localized mostly in lysosomes (CLN1, CLN2, CLN3, CLN5, CLN7, CLN10, CLN12 and CLN13) but also in the Endoplasmic Reticulum (CLN6 and CLN8), or in the cytosol associated to vesicular membranes (CLN4 and CLN14). Some of them such as CLN1 (palmitoyl protein thioesterase 1), CLN2 (tripeptidyl-peptidase 1), CLN5, CLN10 (cathepsin D), and CLN13 (cathepsin F), are lysosomal soluble proteins; others like CLN3, CLN7, and CLN12, have been proposed to be lysosomal transmembrane proteins. In this review, we give our views and attempt to summarize the proposed and confirmed functions of each NCL protein and describe and discuss research results published since the last review on NCL proteins. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".
Collapse
|
|
50
|
Chandrachud U, Walker MW, Simas AM, Heetveld S, Petcherski A, Klein M, Oh H, Wolf P, Zhao WN, Norton S, Haggarty SJ, Lloyd-Evans E, Cotman SL. Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function. J Biol Chem 2015; 290:14361-80. [PMID: 25878248 DOI: 10.1074/jbc.m114.621706] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Indexed: 11/06/2022] Open
Abstract
Abnormal accumulation of undigested macromolecules, often disease-specific, is a major feature of lysosomal and neurodegenerative disease and is frequently attributed to defective autophagy. The mechanistic underpinnings of the autophagy defects are the subject of intense research, which is aided by genetic disease models. To gain an improved understanding of the pathways regulating defective autophagy specifically in juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), a neurodegenerative disease of childhood, we developed and piloted a GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) screening assay to identify, in an unbiased fashion, genotype-sensitive small molecule autophagy modifiers, employing a JNCL neuronal cell model bearing the most common disease mutation in CLN3. Thapsigargin, a sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) Ca(2+) pump inhibitor, reproducibly displayed significantly more activity in the mouse JNCL cells, an effect that was also observed in human-induced pluripotent stem cell-derived JNCL neural progenitor cells. The mechanism of thapsigargin sensitivity was Ca(2+)-mediated, and autophagosome accumulation in JNCL cells could be reversed by Ca(2+) chelation. Interrogation of intracellular Ca(2+) handling highlighted alterations in endoplasmic reticulum, mitochondrial, and lysosomal Ca(2+) pools and in store-operated Ca(2+) uptake in JNCL cells. These results further support an important role for the CLN3 protein in intracellular Ca(2+) handling and in autophagic pathway flux and establish a powerful new platform for therapeutic screening.
Collapse
Affiliation(s)
- Uma Chandrachud
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Mathew W Walker
- the Sir Martin Evans Building, School of Biosciences, Cardiff University, Cardiff CF10 3AX, United Kingdom
| | - Alexandra M Simas
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Sasja Heetveld
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Anton Petcherski
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Madeleine Klein
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Hyejin Oh
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Pavlina Wolf
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Wen-Ning Zhao
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Stephanie Norton
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Stephen J Haggarty
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| | - Emyr Lloyd-Evans
- the Sir Martin Evans Building, School of Biosciences, Cardiff University, Cardiff CF10 3AX, United Kingdom
| | - Susan L Cotman
- From the Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and
| |
Collapse
|