2025-04-10 ノースウェスタン大学
Northwestern Medicine scientists have identified a new set of genes that contribute to the risk of Parkinson’s disease, opening the door to previously untapped drug targets for treating the condition.
<関連情報>
- https://news.northwestern.edu/stories/2025/04/new-key-genes-in-parkinsons-disease-identified-using-crispr-technology/
- https://www.science.org/doi/10.1126/science.adq6650
コマンダー複合体はリソソーム機能を制御し、パーキンソン病のリスクに関与している Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk
Georgia Minakaki, Nathaniel Safren, Bernabe I. Bustos, Steven J. Lubbe, […], and Dimitri Krainc
Science Published:10 Apr 2025
DOI:https://doi.org/10.1126/science.adq6650
Editor’s summary
Variants in the gene GBA1 are associated with reduced lysosomal glucocerebrosidase (GCase) activity and increased risk of developing Parkinson’s disease (PD). However, the incomplete penetrance of GBA1 mutations suggests that there could be genetic modifiers influencing disease risk. Minakaki et al. performed a genome-wide CRISPR interference screening and identified candidate genes that modulated GCase activity. One of the components of the Commander complex, COMMD3, was essential for lysosomal GCase activity, and variants were associated with increased PD risk, suggesting that regulation of this complex might play a role in determining GBA1-mediated PD risk. —Mattia Maroso
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.
