Misfolded GBA/β-glucocerebrosidase impairs ER-quality control by chaperone-mediated autophagy in Parkinson disease

Sheng Han Kuo, Inmaculada Tasset, Ana Maria Cuervo, David Sulzer

Research output: Contribution to journalArticlepeer-review

Abstract

Inhibition of chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation for intracellular proteins, may contribute to pathogenesis in neurodegenerative diseases including Parkinson disease (PD). Pathogenic variants of PD-related proteins that reside in the cytosol, including SNCA/alpha-synuclein, LRRK2 (leucine rich repeat kinase 2), UCHL1 (ubiquitin Cterminal hydrolase 1) and VPS35 (VPS35 retromer complex component), exert inhibitory effects on CMA. Decreased CMA activity has also been reported in sporadic PD patients, consistent with an association between CMA inhibition and PD. We have now reported the first example of CMA dysfunction caused by a non-cytosolic PD-related protein, GBA/β-glucocerebrosidase, the most common genetic risk factor for PD, which uncovers a new role for CMA in endoplasmic reticulum (ER) quality control. .

Original languageEnglish (US)
JournalAutophagy
DOIs
StateAccepted/In press - 2022

Keywords

  • Chaperones
  • ER quality control
  • lysosomal enzymes
  • lysosomes
  • neurodegeneration
  • protein aggregation
  • protein trafficking
  • proteotoxicity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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