ArticleThe Journal of cell biology2025
Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease.
Article in The Journal of cell biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Rictor/mTORC2 signaling pathway protects endogenous neural stem cells to promote recovery after spinal cord injury.Neural regeneration research · 2026Article
- Allosteric switching of CaThe EMBO journal · 2026Article
- O-linked glycan-dependent gating of TPC2 controls lysosomal excitability and organelle remodeling.Nature communications · 2026Article
- Review
- Progress in the study of ion channel function, mechanisms, and mathematical modeling in Parkinson's disease.iScience · 2026Review
- Walnut Peptide KG-7 Alleviates Scopolamine-Induced Memory Deficits and Enhances Paracellular Transport via Tight Junction Modulation in a Mouse Model.Foods (Basel, Switzerland) · 2026Article
- Review
- Mitochondrial Calcium Channels and MAM Interaction in Calcium Homeostasis Dysregulation in Parkinson's Disease.Neurochemical research · 2025Review
- The Two-Pore Channel 2 in Human Physiology and Diseases: Functional Characterisation and Pharmacology.International journal of molecular sciences · 2025Review
Corrections and comments
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Authors and funding
19 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.