Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson’s disease
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.
Authors
- Gustavo J.S. Pereira (ORCID: https://orcid.org/0000-0002-6765-1276)
- Martina Gregori (ORCID: https://orcid.org/0000-0002-0862-2635)
- Si Hang Lei
- Chiao‐Yin Lee (ORCID: https://orcid.org/0000-0003-1117-3006)
- Christian Grimm (ORCID: https://orcid.org/0000-0002-0177-5559)
- Kirsten Harvey (ORCID: https://orcid.org/0000-0002-1291-0728)
- Marco Keller (ORCID: https://orcid.org/0000-0003-4792-3980)
- Franz Bracher (ORCID: https://orcid.org/0000-0003-0009-8629)
- Kai‐Yin Chau (ORCID: https://orcid.org/0000-0002-5797-2922)
- Anthony H.V. Schapira (ORCID: https://orcid.org/0000-0002-3018-3966)
- Matthew E. Gegg (ORCID: https://orcid.org/0000-0001-8093-0723)
- Matthew P. Bostock (ORCID: https://orcid.org/0000-0003-1314-8998)
- Gaiti Hasan (ORCID: https://orcid.org/0000-0001-7194-383X)
- Sandip Patel (ORCID: https://orcid.org/0000-0001-7247-2013)
- Nicholas W. West
- Xinjiang Cai (ORCID: https://orcid.org/0000-0001-8933-7133)
- Sean T. Sweeney (ORCID: https://orcid.org/0000-0003-2673-9578)
- Stephen R. Bolsover
- Robert Allen
Institutions
- Tata Institute of Fundamental Research (IN)
- University of California, Los Angeles (US)
- King's College London (GB)
- National Centre for Biological Sciences (IN)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- The London College (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Institute of Pharmacology (CZ)
- University College London (GB)
- University of York (GB)
- Ludwig-Maximilians-Universität München (DE)
- Universidade Federal de São Paulo (BR)
Publication Details
- Journal
- The Journal of Cell Biology
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1083/jcb.202412055
- Citations
- 7
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 7.82
Funders
- Wellcome Trust
- Parkinson's UK
- University College London
- Deutsche Forschungsgemeinschaft
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Institutes of Health
- Medical Research Council
- Science and Engineering Research Board