Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy

Sheng Han Kuo, Inmaculada Tasset, Melody M. Cheng, Antonio Diaz, Ming Kai Pan, Ori J. Lieberman, Samantha J. Hutten, Roy N. Alcalay, Sangjun Kim, Pilar Ximénez-Embún, Li Fan, Donghoon Kim, Han Seok Ko, Talene Yacoubian, Ellen Kanter, Ling Liu, Guomei Tang, Javier Muñoz, Sergio Pablo Sardi, Aiqun LiLi Gan, Ana Maria Cuervo, David Sulzer

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereabm6393
JournalScience Advances
Volume8
Issue number6
DOIs
StatePublished - Feb 2022

ASJC Scopus subject areas

  • General

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