The neurodegenerative movement disorder Parkinson disease (PD) is prevalent in the aged population. However, the underlying mechanisms that trigger disease are unclear. Increasing work implicates both impaired Ca2+ signalling and lysosomal dysfunction in neuronal demise. Here I aim to connect these distinct processes by exploring the evidence that lysosomal Ca2+ signalling is disrupted in PD. In particular, I highlight defects in lysosomal Ca2+ content and signalling through NAADP-regulated two-pore channels in patient fibroblasts harbouring mutations in the PD-linked genes, GBA1 and LRRK2. As an emerging contributor to PD pathogenesis, the lysosomal Ca2+ signalling apparatus could represent a novel therapeutic target.
Keywords: Ca2+; GBA1; LRRK2; Lysosomes; NAADP; Parkinson disease; TPC1; TPC2; TRPML1.