Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-04-10 DOI:10.1126/science.adq6650

Georgia Minakaki, Nathaniel Safren, Bernabe I. Bustos, Steven J. Lubbe, Niccolò E. Mencacci, Dimitri Krainc

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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.

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指挥官复合体调节溶酶体功能并与帕金森病风险有关

GBA1变异导致溶酶体糖脑苷酶（GCase）活性降低，是帕金森病（PD）和路易体痴呆（DLB）的常见危险因素。GBA1变异的不完全外显率表明其他基因有助于PD和DLB的表现。通过全基因组CRISPR干扰筛选，我们鉴定出铜代谢含MURR1结构域3 （COMMD3）蛋白作为GCase和溶酶体活性的修饰因子，该蛋白是COMMD/coil -coil结构域蛋白22 (CCDC22)/CCDC93 （CCC）和Commander复合物的一个组成部分。COMMD3的缺失增加了溶酶体蛋白通过细胞外囊泡的释放，导致它们向内溶酶体的递送受损，从而导致溶酶体功能障碍。Commander基因家族的罕见变异与PD风险增加有关。因此，COMMD基因和相关复合物调节溶酶体稳态，并可能代表PD和其他与溶酶体功能障碍相关的神经退行性疾病的修饰因子。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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