In EDS ansehen

Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone

Gespeichert in:
Bibliographische Detailangaben
Titel: Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone
Autoren: Dong Kyu Kim, Tomoko Nakazato, Phil Hyu Lee, Kenya Nishioka, Byung Chul Jung, Kazuaki Kanai, Nobutaka Hattori, Yuanzhe Li, Morio Ueyama, Mitsuyoshi Nakatani, Hiroyo Yoshino, Ryusuke Sakai, Manabu Funayama, Han Soo Yoo, YuHong Fu, Seung-Jae Lee, Woojin S. Kim, Minsun Choi, Satoko Sekimoto, Yoshitaka Nagai, Kyu Won Oh, Glenda M. Halliday, Jun Sung Lee, Mari Suzuki, Sergio Pablo Sardi, He Jin Lee, Hideki Mochizuki, Shin Ichiro Kubo
Weitere Verfasser: Jun Sung Lee, Kazuaki Kanai, Mari Suzuki, Woojin S Kim, Han Soo Yoo, YuHong Fu, Dong-Kyu Kim, Byung Chul Jung, Minsun Choi, Kyu Won Oh, Yuanzhe Li, Mitsuyoshi Nakatani, Tomoko Nakazato, Satoko Sekimoto, Manabu Funayama, Hiroyo Yoshino, Shin-Ichiro Kubo, Kenya Nishioka, Ryusuke Sakai, Morio Ueyama, Hideki Mochizuki, He-Jin Lee, Sergio Pablo Sardi, Glenda M Halliday, Yoshitaka Nagai, Phil Hyu Lee, Nobutaka Hattori, Seung-Jae Lee, Yoo, Han Soo
Quelle: Brain. 142:2845-2859
Verlagsinformationen: Oxford University Press (OUP), 2019.
Publikationsjahr: 2019
Schlagwörter: Male, 0301 basic medicine, Animals, Genetically Modified, Point Mutation, Gene Knockout Techniques, Protein Interaction Mapping, Cerebroside-Sulfatase / physiology, Drosophila Proteins, Caenorhabditis elegans / genetics, Drosophila Proteins / deficiency, alpha-Synuclein / metabolism, Cells, Cultured, Genes, Dominant, 2. Zero hunger, 0303 health sciences, Cultured, Molecular Chaperones / metabolism, Cerebroside-Sulfatase / genetics, Pathological / genetics, Recombinant Proteins / metabolism, Parkinson Disease / metabolism, Brain, molecular chaperone, Middle Aged, Dementia / blood, arylsulfatase A, Pedigree, 3. Good health, Dementia / etiology, Drosophila melanogaster, Parkinson Disease / genetics, Female, Cerebroside-Sulfatase / blood, Drosophila Proteins / genetics, Adult, Cells, Mutation, Missense, Genetically Modified, Brain / enzymology, 03 medical and health sciences, α-synuclein, Parkinson Disease / psychology, Caenorhabditis elegans Proteins / metabolism, Caenorhabditis elegans / metabolism, Animals, Humans, Dominant, Drosophila melanogaster / metabolism, Missense, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cerebroside-Sulfatase, Aged, protein aggregation and propagation, Drosophila Proteins / metabolism, Protein Aggregation, Caenorhabditis elegans Proteins / genetics, Drosophila melanogaster / genetics, Genes, Mutation, Parkinson's disease, Dementia, Molecular Chaperones
Beschreibung: Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson’s disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson’s disease. Plasma ARSA protein levels were changed in Parkinson’s disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson’s disease pathogenesis, acting as a molecular chaperone for α-synuclein.
Publikationsart: Article
Sprache: English
ISSN: 1460-2156
0006-8950
DOI: 10.1093/brain/awz205
Zugangs-URL: https://pubmed.ncbi.nlm.nih.gov/31312839
Rights: OUP Standard Publication Reuse
CC BY NC ND
Dokumentencode: edsair.doi.dedup.....cdb2405a6d9997dbfd8f74e2e574a6fc
Datenbank: OpenAIRE
Beschreibung
Abstract:Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson’s disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson’s disease. Plasma ARSA protein levels were changed in Parkinson’s disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson’s disease pathogenesis, acting as a molecular chaperone for α-synuclein.
ISSN:14602156
00068950
DOI:10.1093/brain/awz205