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

Academic Article

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.
  • Published In

  • Science Advances  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 26963549
  • Author List

  • Kuo SH; Tasset I; Cheng MM; Diaz A; Pan MK; Lieberman OJ; Hutten SJ; Alcalay RN; Kim S; Ximénez-Embún P
  • Volume

  • 8
  • Issue

  • 6