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

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/beta-glucocerebrosidase, the most common genetic risk factor for PD, which uncovers a new role for CMA in endoplasmic reticulum (ER) quality control.

Automated summary

Inhibition of chaperone-mediated autophagy (CMA) may play a significant role in neurodegenerative diseases, including Parkinson's disease (PD). PD-related proteins in the cytosol have been found to inhibit CMA, and decreased CMA activity has been observed in sporadic PD patients. Additionally, dysfunction of CMA caused by the non-cytosolic PD-related protein GBA has been reported, revealing a new role for CMA in endoplasmic reticulum quality control.