Alternate Splicing Directs PMCA2 to Lysosomes and is Linked to Neurodegeneration
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Plasma membrane calcium ATPase (PMCAs) are believed to function exclusively at the plasma membrane where they expel calcium from the cytosol. We have unexpectedly identified a splice variant-dependent localisation of the PMCA isoform PMCA2 to the lysosome, where it forms an evolutionarily conserved complex with NPC1, the lysosomal membrane protein defective in the rare lysosomal storage disease Niemann-Pick disease type C (NPC). This interaction is involved in maintaining lysosomal calcium levels, and we have found its disruption contributes to the pathophysiology of both NPC and Parkinson’s disease. Our findings uncover a previously unrecognised intracellular role for PMCA2, revealing a shared mechanism of lysosomal calcium and lipid regulation with direct relevance to neurodegeneration.
