| Title: | Commander complex regulates lysosomal function and is implicated in Parkinson's disease risk |
| Journal: | Science |
| Published: | 10 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40209002/ |
| DOI: | https://doi.org/10.1126/science.adq6650 |
Publication 14717
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Abstract
Variants in GBA1 resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of GBA1 variants suggests that additional genes contribute to PD and DLB manifestation. By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain-containing 3 (COMMD3) protein, a component of the COMMD/coiled-coil domain-containing protein 22 (CCDC22)/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity. Loss of COMMD3 increased the release of lysosomal proteins through extracellular vesicles, leading to their impaired delivery to endolysosomes and consequent lysosomal dysfunction. Rare variants in the Commander gene family were associated with increased PD risk. Thus, COMMD genes and related complexes regulate lysosomal homeostasis and may represent modifiers in PD and other neurodegenerative diseases associated with lysosomal dysfunction.</p>
8 Keywords
- Adaptor Proteins, Signal Transducing
- Genetic Predisposition to Disease
- Glucosylceramidase
- HEK293 Cells
- Humans
- Lewy Body Disease
- Lysosomes
- Parkinson Disease
6 Authors
- Georgia Minakaki
- Nathaniel Safren
- Bernabe I Bustos
- Steven J Lubbe
- Niccolò E Mencacci
- Dimitri Krainc
1 Application
| Application ID | Title |
|---|---|
| 78210 | Replication of candidate genes associated with Parkinon's disease and cutaneous malignant melanoma using whole-exome sequencing data. |
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