The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.

Autor: Jones-Tabah J; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, Canada., He K; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada., Senkevich K; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, Canada., Karpilovsky N; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada., Deyab G; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada., Cousineau Y; Department of Neurology and Neurosurgery, McGill University, Montréal, Canada., Nikanorova D; Research Department, Bioinformatics Institute, Saint-Petersburg, Russia., Goldsmith T; Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada., Del Cid Pellitero E; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada., Chen CX; Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada., Luo W; Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada., You Z; Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada., Abdian N; Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada., Pietrantonio I; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada., Goiran T; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada., Ahmad J; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, Canada., Ruskey JA; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, Canada., Asayesh F; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada.; Department of Human Genetics, McGill University, Montréal, Canada., Spiegelman D; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada., Waters C; Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, NY, USA., Monchi O; Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.; Département de radiologie, radio-oncologie et médecine nucléaire, Université de Montréal, Montréal, QC, Canada.; Centre de recherche de l'Institut universitaire de gériatrie de Montréal, Montréal, QC, Canada., Dauvilliers Y; National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France., Dupré N; Neuroscience Axis, CHU de Québec - Université Laval, Quebec City, G1V 4G2, Canada.; Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, G1V 0A6, Canada., Miliukhina I; Institute of the Human Brain of RAS, St. Petersburg, Russia., Timofeeva A; First Pavlov State Medical University of St. Petersburg, Saint-Petersburg, Russia., Emelyanov A; First Pavlov State Medical University of St. Petersburg, Saint-Petersburg, Russia., Pchelina S; First Pavlov State Medical University of St. Petersburg, Saint-Petersburg, Russia., Greenbaum L; Institute of the Human Brain of RAS, St. Petersburg, Russia.; First Pavlov State Medical University of St. Petersburg, Saint-Petersburg, Russia.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Hassin-Baer S; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel.; The Movement Disorders Institute, Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel., Alcalay RN; Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, NY, USA.; Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel., Milnerwood A; Department of Neurology and Neurosurgery, McGill University, Montréal, Canada., Durcan TM; Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada., Gan-Or Z; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada.; Department of Human Genetics, McGill University, Montréal, Canada., Fon EA; McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Québec, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, Canada.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 15. Date of Electronic Publication: 2023 Nov 15.
DOI: 10.1101/2023.11.11.566693
Abstrakt: 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. 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 and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. 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. 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.
Databáze: MEDLINE