The Patel Lab with Martina Gregori suggests blocking lysosomal ion channel for treating Parkinsonism

The Patel lab, led by UCL CDB's Head of Research Department, Dr Sandip Patel, has published in the Journal of Cell Biology a new study on calcium and Parkinson’s disease.  The paper was based on the PhD research dissertation of first author Martina Gregori, who was a Wellcome Trust neuroscience student.

The main finding is that the entry of calcium ions (Ca²⁺) into neurons is disrupted by mutation of the LRRK2 gene linked to Parkinson’s. This can be reversed by pharmacological agents that target the lysosomal ion channel, TPC2, including one recently-identified compound that unusually ‘switches’ the ion selectivity of TPC2.  Another finding, using flies as the model organism, is that TPC2 disrupts dopaminergic circuits linked to vision and movement, similar to the mutant LRRK2 gene. Again, this is reversed by biasing TPC2.

Overall, the study links fluxes of ions at the cell surface to those in lysosomes and the function of dopaminergic neurons that degenerate in Parkinson’s.   Hence, drugging TPC2 might one day help combat the disease.

The images show: (left) epifluorescence image of induced pluripotent stem cell-derived dopaminergic neurons generated from a person living with LRRK2-Parkinsons and labelled with a chemical calcium indicator; and (right) confocal image of a fly S2R+ cell expressing TPC2 fused to a genetically-encoded calcium indicator.

The research, funded by The Wellcome Trust and Parkinson’s UK, was very much a  collaborative effort, featuring substantial input from Gustavo Pereira, a post-doc in the Patel Lab and an Associate Professor from Sao Paulo, Brazil, and the labs of Sean Sweeney (University of York) and Anthony Schapira (Institute of Neurology, UCL). Additional contributions included those from collaborators at the UCL School of Pharmacy, King’s College London, University of California, Los Angeles,  Ludwig Maximilian University and the National Centre for Biological Sciences (India). 

The full text of the paper is at:  Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson's disease. Gregori M, Pereira GJS, Allen R, West N, Chau KY, Cai X, Bostock MP, Bolsover SR, Keller M, Lee CY, Lei SH, Harvey K, Bracher F, Grimm C, Hasan G, Gegg ME, Schapira AHV, Sweeney ST, Patel S. J. Cell Biol. 2025 Jun 2;224(6):e202412055. doi: 10.1083/jcb.202412055. Epub 2025 Apr 25.PMID: 40279672