Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease

Soojin Kim, Yvette C. Wong, Fanding Gao and Dimitri Krainc ()
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Soojin Kim: Northwestern University Feinberg School of Medicine
Yvette C. Wong: Northwestern University Feinberg School of Medicine
Fanding Gao: Northwestern University Feinberg School of Medicine
Dimitri Krainc: Northwestern University Feinberg School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22113-3

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