Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson’s disease
Martina Gregori, Gustavo J.S. Pereira, Robert Allen, Nicholas W. West, Kai‐Yin Chau, Xinjiang Cai, Matthew P. Bostock, Stephen R. Bolsover, Marco Keller, Chiao‐Yin Lee, Si Hang Lei, Kirsten Harvey, Franz Bracher, Christian Grimm, Gaiti Hasan, Matthew E. Gegg, Anthony H.V. Schapira, Sean T. Sweeney, Sandip Patel
Abstract
Parkinson's disease results from degeneration of dopaminergic neurons in the midbrain, but the underlying mechanisms are unclear. Here, we identify novel crosstalk between depolarization-induced entry of Ca2+ and lysosomal cation release in maintaining dopaminergic neuronal function. The common disease-causing G2019S mutation in LRRK2 selectively exaggerated Ca2+ entry in vitro. Chemical and molecular strategies inhibiting the lysosomal ion channel TPC2 reversed this. Using Drosophila, which lack TPCs, we show that the expression of human TPC2 phenocopied LRRK2 G2019S in perturbing dopaminergic-dependent vision and movement in vivo. Mechanistically, dysfunction required an intact pore, correct subcellular targeting and Rab interactivity of TPC2. Reducing Ca2+ permeability with a novel biased TPC2 agonist corrected deviant Ca2+ entry and behavioral defects. Thus, both inhibition and select activation of TPC2 are beneficial. Functional coupling between lysosomal cation release and Ca2+ influx emerges as a potential druggable node in Parkinson's disease.