The role of Plasma Membrane Calcium ATPases (PMCAs) in neurodegenerative disorders

Selective degeneration of differentiated neurons in the brain is the unifying feature of neurodegenerative disorders such as Parkinson's disease (PD) or Alzheimer's disease (AD). A broad spectrum of evidence indicates that initially subtle, but temporally early calcium dysregulation may be central to the selective neuronal vulnerability observed in these slowly progressing, chronic disorders. Moreover, it has long been evident that excitotoxicity and its major toxic effector mechanism, neuronal calcium overload, play a decisive role in the propagation of secondary neuronal death after acute brain injury from trauma or ischemia. Under physiological conditions, neuronal calcium homeostasis is maintained by a fine-tuned interplay between calcium influx and releasing mechanisms (Ca2+-channels), and calcium efflux mechanisms (Ca2+-pumps and-exchangers). Central functional components of the calcium efflux machinery are the Plasma Membrane Calcium ATPases (PMCAs), which represent high-affinity calcium pumps responsible for the ATP-dependent removal of calcium out of the cytosol. Beyond a growing body of experimental evidence, it is their high expression level, their independence of secondary ions or membrane potential, their profound redox regulation and autoregulation, their postsynaptic localization in close proximity to the primary mediators of pathological calcium influx, i.e. NMDA receptors, as well as evolutionary considerations which all suggest a pivotal role of the PMCAs in the etiology of neurodegeneration and make them equally challenging and alluring candidates for drug development. This review aims to summarize the recent literature on the role of PMCAs in the pathogenesis of neurodegenerative disorders.