Connecting Ca²⁺ and lysosomes to Parkinson disease

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.