Evidence for a role of plasma membrane calcium pumps in neurodegenerative disease: Recent developments

[Display omitted] •PMCA dysfunction impairs precise Ca2+ signaling in neurons producing neurotoxicity.•Loss of PMCA function accompanies excitotoxicity and contributes to ischemia and spinal cord pathology.•PMCA2 and PMCA3 mutations are linked to cerebellar ataxias and sensory neuron diseases.•PMCA mutations are often pathogenic when combined with modifier gene mutations.•Decreases in PMCA function during aging and in AD may accelerate neurodegeneration. Plasma membrane Ca2+ ATPases (PMCAs) are a major system for calcium extrusion from all cells. Different PMCA isoforms and splice variants are involved in the precise temporal and spatial handling of Ca2+ signals and the re-establishment of resting Ca2+ levels in the nervous system. Lack or inappropriate expression of specific PMCAs leads to characteristic neuronal phenotypes, which may be reciprocally exacerbated by genetic predisposition through alleles in other genes that modify PMCA interactions, regulation, and function. PMCA dysfunction is often poorly compensated in neurons and may lead to changes in synaptic transmission, altered excitability and, with long-term calcium overload, eventual cell death. Decrease and functional decline of PMCAs are hallmarks of neurodegeneration during aging, and mutations in specific PMCAs are responsible for neuronal dysfunction and accelerated neurodegeneration in many sensory and cognitive diseases.