Abstract
Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. In this study, we demonstrate that mitochondria-lysosome contacts can dynamically form in the soma, axons, and dendrites of human neurons, allowing for their bidirectional crosstalk. Parkinson’s disease patient derived neurons harboring mutant GBA1 exhibited prolonged mitochondria-lysosome contacts due to defective modulation of the untethering protein TBC1D15, which mediates Rab7 GTP hydrolysis for contact untethering. This dysregulation was due to decreased GBA1 (β-glucocerebrosidase (GCase)) lysosomal enzyme activity in patient derived neurons, and could be rescued by increasing enzyme activity with a GCase modulator. These defects resulted in disrupted mitochondrial distribution and function, and could be further rescued by TBC1D15 in Parkinson’s patient derived GBA1-linked neurons. Together, our work demonstrates a potential role of mitochondria-lysosome contacts as an upstream regulator of mitochondrial function and dynamics in midbrain dopaminergic neurons in GBA1-linked Parkinson’s disease.
Highlights
Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown
Our results suggest that upregulation of TBC1D15 in Parkinson’s disease (PD) patient mutant GBA1 neurons is sufficient to rescue the misregulation of M–L contact untethering, as well as downstream defects in mitochondrial dynamics and function
Our study demonstrates that M–L contact sites dynamically form in human neurons, and further investigates their role in neurons from patients with GBA1-linked PD
Summary
Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. Parkinson’s disease patient derived neurons harboring mutant GBA1 exhibited prolonged mitochondria-lysosome contacts due to defective modulation of the untethering protein TBC1D15, which mediates Rab[7] GTP hydrolysis for contact untethering. This dysregulation was due to decreased GBA1 (β-glucocerebrosidase (GCase)) lysosomal enzyme activity in patient derived neurons, and could be rescued by increasing enzyme activity with a GCase modulator. This resulted in decreased levels of the untethering protein TBC1D15 which normally mediates Rab[7] GTP hydrolysis for contact untethering These defects resulted in disrupted mitochondrial distribution and function, but could be rescued by TBC1D15 in Parkinson’s patient GBA1-linked neurons. Our work identifies an important role for M–L contact sites in human neurons and in GBA1-linked PD pathophysiology
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