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

• DOI: 10.1126/sciadv.abm6393
• Publication Date: 2022-06-07T14:00:42Z
• Authors: 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 Li; Li Gan; Ana Maria Cuervo; David Sulzer
• Keywords: Chaperone (clinical)

The most common genetic risk factors for Parkinson’s disease (PD) are a set of heterozygous mutant (MT) alleles the GBA1 gene that encodes β-glucocerebrosidase (GCase), an enzyme normally trafficked through ER/Golgi apparatus to lysosomal lumen. We found half GCase in lysosomes from postmortem human GBA-PD brains was present on surface and this mislocalization depends pentapeptide motif used target cytosolic protein degradation by chaperone-mediated autophagy (CMA). MT at inhibits CMA, causing accumulation CMA substrates including α-synuclein. Single-cell transcriptional analysis proteomics patients confirmed reduced activity proteome changes comparable those CMA-deficient mouse brain. Loss rescued primary substantia nigra dopaminergic neurons GCase–induced neuronal death. conclude block function produce α-synuclein accumulation.