Targeting Lysosomal pH Restores Mitochondrial Quality Control in GBA1-Mutant Parkinson’s Disease

Heterozygous mutations in the Glucocerebrosidase gene ( GBA1 ), encoding the lysosomal hydrolase β-glucocerebrosidase (GCase), are a genetic risk factor for Parkinson’s disease (PD). To explore the pathophysiological consequences of these mutations, we have used fibroblasts and dopaminergic neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with GBA1 related PD. GCase activity, lysosomal acidification, protease activity, mitophagy and mitochondrial bioenergetic function were all impaired. Mitochondria were fragmented, with reduced membrane potential and oxygen consumption. We propose that impaired bioenergetic function is a consequence of impaired lysosomal acidification and compromised mitophagy. The V-ATPase complex drives lysosomal acidification. Its assembly is regulated by MTORC1, which is constitutively phosphorylated in mutant cells. FLIM-FRET measurements confirmed impaired V-ATPase assembly which reversed following rapamycin treatment. Acidic nanoparticles, which accumulate in lysosomes, rescued lysosomal pH, and restored mitophagy and mitochondrial membrane potential in GBA1 mutant dopaminergic neurons. These data identify a core pathway as a potential therapeutic target for the treatment of GBA1 -mediated Parkinson’s Disease.