Variant ‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis

Glucocerenrosidase1 (GBA1) mutations cause disruptions in endoplasmic reticulum (ER) and lysosome-related proteostasis pathways in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons. SevereGBA1 mutations lead to increased ER stress (increased binding immunoglobulin protein (BiP) and protein disulfide isomerase (PDI) levels), total ubiquitination rates, and unfolded protein response (UPR). Defective chaperone-mediated autophagy (decreased heat-shock cognate protein 70 (HSC70) levels and decreased co-localization of lysosomal-associated membrane protein 2A (LAMP2A) and HSC70) is observed in iPSC-derived dopaminergic neurons with mild homozygousGBA1 mutations. Decreased autophagosome formation (decreased microtubule-associated protein light chain 3A (LC3) levels) is observed in iPSC-derived dopaminergic neurons with homozygous N370S and D409HGBA1 mutations, while fusion defects (decreased lysosomal-associated membrane protein 1 (LAMP1) and LC3 co-localization) are observed in neurons with homozygous L444PGBA1 mutation. SevereGBA1 mutations trigger the accumulation of monomeric and oligomeric forms of α-synuclein.GBA1 mutations increase the release of α-synuclein from iPSC-derived dopaminergic neurons. AbstractGlucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H)GBA1 mutations have different PD phenotypes, with differences in age at di...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research