The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons
Abstract Background Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson’s disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-11-01
|
| Series: | Molecular Neurodegeneration |
| Online Access: | https://doi.org/10.1186/s13024-024-00779-9 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850134300150726656 |
|---|---|
| author | Jace Jones-Tabah Kathy He Nathan Karpilovsky Konstantin Senkevich Ghislaine Deyab Isabella Pietrantonio Thomas Goiran Yuting Cousineau Daria Nikanorova Taylor Goldsmith Esther del Cid Pellitero Carol X.-Q. Chen Wen Luo Zhipeng You Narges Abdian Jamil Ahmad Jennifer A. Ruskey Farnaz Asayesh Dan Spiegelman Stanley Fahn Cheryl Waters Oury Monchi Yves Dauvilliers Nicolas Dupré Irina Miliukhina Alla Timofeeva Anton Emelyanov Sofya Pchelina Lior Greenbaum Sharon Hassin-Baer Roy N. Alcalay Austen Milnerwood Thomas M. Durcan Ziv Gan-Or Edward A. Fon |
| author_facet | Jace Jones-Tabah Kathy He Nathan Karpilovsky Konstantin Senkevich Ghislaine Deyab Isabella Pietrantonio Thomas Goiran Yuting Cousineau Daria Nikanorova Taylor Goldsmith Esther del Cid Pellitero Carol X.-Q. Chen Wen Luo Zhipeng You Narges Abdian Jamil Ahmad Jennifer A. Ruskey Farnaz Asayesh Dan Spiegelman Stanley Fahn Cheryl Waters Oury Monchi Yves Dauvilliers Nicolas Dupré Irina Miliukhina Alla Timofeeva Anton Emelyanov Sofya Pchelina Lior Greenbaum Sharon Hassin-Baer Roy N. Alcalay Austen Milnerwood Thomas M. Durcan Ziv Gan-Or Edward A. Fon |
| author_sort | Jace Jones-Tabah |
| collection | DOAJ |
| description | Abstract Background Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson’s disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Methods Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines, induced pluripotent stem cell-derived dopaminergic neurons and midbrain organoids and assessed lysosomal activity and the handling of aggregated synuclein fibrils. Results We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. Conclusions These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein. |
| format | Article |
| id | doaj-art-e2786b44f0ab42b995b54fb1787459cd |
| institution | OA Journals |
| issn | 1750-1326 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-e2786b44f0ab42b995b54fb1787459cd2025-08-20T02:31:44ZengBMCMolecular Neurodegeneration1750-13262024-11-0119112110.1186/s13024-024-00779-9The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neuronsJace Jones-Tabah0Kathy He1Nathan Karpilovsky2Konstantin Senkevich3Ghislaine Deyab4Isabella Pietrantonio5Thomas Goiran6Yuting Cousineau7Daria Nikanorova8Taylor Goldsmith9Esther del Cid Pellitero10Carol X.-Q. Chen11Wen Luo12Zhipeng You13Narges Abdian14Jamil Ahmad15Jennifer A. Ruskey16Farnaz Asayesh17Dan Spiegelman18Stanley Fahn19Cheryl Waters20Oury Monchi21Yves Dauvilliers22Nicolas Dupré23Irina Miliukhina24Alla Timofeeva25Anton Emelyanov26Sofya Pchelina27Lior Greenbaum28Sharon Hassin-Baer29Roy N. Alcalay30Austen Milnerwood31Thomas M. Durcan32Ziv Gan-Or33Edward A. Fon34Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityDepartment of Neurology and Neurosurgery, McGill UniversityResearch Department, Bioinformatics InstituteEarly Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityEarly Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill UniversityEarly Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill UniversityEarly Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill UniversityEarly Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityDepartment of Neurology, College of Physicians and Surgeons, Columbia University Medical CenterDepartment of Neurology, College of Physicians and Surgeons, Columbia University Medical CenterDepartment of Neurology and Neurosurgery, McGill UniversitySleep Unit, Department of Neurology, National Reference Center for Narcolepsy, Gui-de-Chauliac Hospital, CHU Montpellier, University of MontpellierNeuroscience Axis, CHU de Québec – Université Laval, Institute of the Human Brain of RASFirst Pavlov State Medical, University of St. PetersburgFirst Pavlov State Medical, University of St. PetersburgFirst Pavlov State Medical, University of St. PetersburgInstitute of the Human Brain of RASSackler Faculty of Medicine, Tel Aviv UniversityDepartment of Neurology, College of Physicians and Surgeons, Columbia University Medical CenterDepartment of Neurology and Neurosurgery, McGill UniversityEarly Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityNeurodegenerative Diseases Group, Department of Neurology and Neurosurgery, McGill Parkinson Program, Montreal Neurological Institute-Hospital, McGill UniversityAbstract Background Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson’s disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Methods Here, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines, induced pluripotent stem cell-derived dopaminergic neurons and midbrain organoids and assessed lysosomal activity and the handling of aggregated synuclein fibrils. Results We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. Conclusions These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.https://doi.org/10.1186/s13024-024-00779-9 |
| spellingShingle | Jace Jones-Tabah Kathy He Nathan Karpilovsky Konstantin Senkevich Ghislaine Deyab Isabella Pietrantonio Thomas Goiran Yuting Cousineau Daria Nikanorova Taylor Goldsmith Esther del Cid Pellitero Carol X.-Q. Chen Wen Luo Zhipeng You Narges Abdian Jamil Ahmad Jennifer A. Ruskey Farnaz Asayesh Dan Spiegelman Stanley Fahn Cheryl Waters Oury Monchi Yves Dauvilliers Nicolas Dupré Irina Miliukhina Alla Timofeeva Anton Emelyanov Sofya Pchelina Lior Greenbaum Sharon Hassin-Baer Roy N. Alcalay Austen Milnerwood Thomas M. Durcan Ziv Gan-Or Edward A. Fon The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons Molecular Neurodegeneration |
| title | The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons |
| title_full | The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons |
| title_fullStr | The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons |
| title_full_unstemmed | The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons |
| title_short | The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons |
| title_sort | parkinson s disease risk gene cathepsin b promotes fibrillar alpha synuclein clearance lysosomal function and glucocerebrosidase activity in dopaminergic neurons |
| url | https://doi.org/10.1186/s13024-024-00779-9 |
| work_keys_str_mv | AT jacejonestabah theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT kathyhe theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT nathankarpilovsky theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT konstantinsenkevich theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT ghislainedeyab theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT isabellapietrantonio theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT thomasgoiran theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT yutingcousineau theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT darianikanorova theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT taylorgoldsmith theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT estherdelcidpellitero theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT carolxqchen theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT wenluo theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT zhipengyou theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT nargesabdian theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT jamilahmad theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT jenniferaruskey theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT farnazasayesh theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT danspiegelman theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT stanleyfahn theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT cherylwaters theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT ourymonchi theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT yvesdauvilliers theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT nicolasdupre theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT irinamiliukhina theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT allatimofeeva theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT antonemelyanov theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT sofyapchelina theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT liorgreenbaum theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT sharonhassinbaer theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT roynalcalay theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT austenmilnerwood theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT thomasmdurcan theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT zivganor theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT edwardafon theparkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT jacejonestabah parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT kathyhe parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT nathankarpilovsky parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT konstantinsenkevich parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT ghislainedeyab parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT isabellapietrantonio parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT thomasgoiran parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT yutingcousineau parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT darianikanorova parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT taylorgoldsmith parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT estherdelcidpellitero parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT carolxqchen parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT wenluo parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT zhipengyou parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT nargesabdian parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT jamilahmad parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT jenniferaruskey parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT farnazasayesh parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT danspiegelman parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT stanleyfahn parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT cherylwaters parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT ourymonchi parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT yvesdauvilliers parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT nicolasdupre parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT irinamiliukhina parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT allatimofeeva parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT antonemelyanov parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT sofyapchelina parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT liorgreenbaum parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT sharonhassinbaer parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT roynalcalay parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT austenmilnerwood parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT thomasmdurcan parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT zivganor parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons AT edwardafon parkinsonsdiseaseriskgenecathepsinbpromotesfibrillaralphasynucleinclearancelysosomalfunctionandglucocerebrosidaseactivityindopaminergicneurons |