葡萄糖脑苷酶
自噬
生物
黑质
细胞生物学
突变体
高尔基体
伴侣(临床)
α-突触核蛋白
多巴胺能
分子生物学
帕金森病
生物化学
基因
多巴胺
内质网
细胞凋亡
神经科学
疾病
病理
医学
作者
Sheng‐Han Kuo,Inmaculada Tasset,Melody M. Cheng,Antonio Díaz,Ming‐Kai Pan,Ori J. Lieberman,Samantha J. Hutten,Roy N. Alcalay,Sangjune Kim,Pilar Ximénez-Embún,Li Fan,Dong-Hoon Kim,Han Seok Ko,Talene A. Yacoubian,Ellen Kanter,Ling Liu,Guomei Tang,Javier Muñoz,S. Pablo Sardi,Aiqun Li,Li Gan,Ana María Cuervo,David Sulzer
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2022-02-11
卷期号:8 (6)
被引量:67
标识
DOI:10.1126/sciadv.abm6393
摘要
The most common genetic risk factors for Parkinson's disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes β-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from postmortem human GBA-PD brains was present on the lysosomal surface and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). MT GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including α-synuclein. Single-cell transcriptional analysis and proteomics of brains from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif rescued primary substantia nigra dopaminergic neurons from MT GCase-induced neuronal death. We conclude that MT GBA1 alleles block CMA function and produce α-synuclein accumulation.
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