Misregulation of Mitochondria-Lysosome Contact Sites in GBA-linked Parkinson’s Disease


Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. We used super-resolution and live-cell microscopy in human iPSC-derived neurons to demonstrate that mitochondria-lysosome contacts can dynamically form in the soma, axons, and dendrites of human neurons, allowing for their bidirectional crosstalk. To examine these contacts in diseased neurons, we have focused on Parkinson’s disease that is characterized by preferential degeneration of midbrain dopaminergic neurons. Specifically, we examined Parkinson’s disease patient neurons harboring mutations in GBA1 gene that codes for lysosomal enzyme β-glucocerebrosidase (GCase). Interestingly, we found prolonged mitochondria-lysosome contacts in GBA1-PD neurons due to defective modulation of the protein TBC1D15, which mediates Rab7 GTP hydrolysis for contact untethering. Importantly, these defects in mitochondria-lysosome contacts resulted in disrupted mitochondrial distribution and function that was partially ameliorated by expression of TBC1D15 in PD patient neurons. Moreover, we found that dysregulation of TBC1D15 in patient neurons was partially rescued by correcting GCase activity with a small molecule activator of GCase. Together, our work demonstrates an important role of mitochondria-lysosome contacts as a regulator of mitochondrial function and dynamics in midbrain dopaminergic neurons, contributing to the pathogenesis of Parkinson’s disease.

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