| Title: | The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons |
| Journal: | Molecular Neurodegeneration |
| Published: | 25 Nov 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39587654/ |
| DOI: | https://doi.org/10.1186/s13024-024-00779-9 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11587650 |
Publication 14264
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
BackgroundVariants 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.MethodsHere, 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.ResultsWe 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.ConclusionsThese 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.</p>
7 Keywords
- Cathepsin B
- Dopaminergic Neurons
- Glucosylceramidase
- Humans
- Lysosomes
- Parkinson Disease
- alpha-Synuclein
35 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 45551 | Mechanistic modelling of neurodevelopment, neuroplasticity, and neurodegeneration |
Enabling scientific discoveries that improve human health