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Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease

Gregori, Martina; Pereira, Gustavo JS; Allen, Robert; West, Nicholas; Chau, Kai-Yin; Cai, Xinjiang; Bostock, Matthew P; ... Patel, Sandip; + view all (2025) Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease. Journal of Cell Biology , 224 (6) , Article e202412055. 10.1083/jcb.202412055. Green open access

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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.

Type: Article
Title: Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1083/jcb.202412055
Publisher version: https://doi.org/10.1083/jcb.202412055
Language: English
Additional information: © 2025 Gregori et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/)
Keywords: Animals, Lysosomes, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Humans, Parkinson Disease, Calcium, Dopaminergic Neurons, Calcium Channels, Drosophila melanogaster, Drosophila Proteins, Disease Models, Animal, Dopamine, Mutation, HEK293 Cells, Calcium Signaling
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10207875
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