Two-pore channels in Parkinson disease

Two-pore channels (TPCs) are endolysosomal ion channels that mediate Ca²⁺ signals in response to the Ca²⁺-mobilising messenger nicotinic acid adenine dinucleotide phosphate (NAADP). The human isoforms, TPC1 and TPC2 are found on acidic vesicles and are thought to regulate trafficking events within the endolysosomal system. Parkinson disease is a progressive neurodegenerative disorder, which in some cases is caused by mutations in LRKK2, which encodes a large modular protein implicated in endolysosomal trafficking; but the mechanisms giving rise to the disease are unclear. On page 232, Sandip Patel and colleagues examine primary fibroblasts from Parkinson patients with the common LRKK2 G2019S mutation. Using different approaches to analyse the lysosomal system in these cells, they identify pronounced changes in lysosomal morphology that are dependent on the kinase activity of LRRK2. Because the observed changes are reminiscent of those described for TPC2 overexpression, the authors ask whether TPC2 is linked to mutant LRKK2 function. Indeed, when they silence TPC2 in the patient fibroblasts by using small interfering RNAs or pharmacological inhibition of TPC regulators, lysosomal morphology is normalised, suggesting that aberrant TPC signalling and the associated changes in Ca²⁺ flux contribute to pathogenesis. Thus, this works establishes the first link between TPCs and Parkinson disease and presents TPC2 as a new target for therapeutic intervention in Parkinson disease.