Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury

Abstract

Dysfunction and death of spinal cord neurons are critical determinants of neurological deficits in various pathological conditions, including multiple sclerosis (MS) and spinal cord injury. Yet, the molecular mechanisms underlying neuronal/axonal damage remain undefined. Our previous studies raised the possibility that a decrease in the levels of plasma membrane calcium ATPase isoform 2 (PMCA2), a major pump extruding calcium from neurons, promotes neuronal pathology in the spinal cord during experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and after spinal cord trauma. However, the causal relationship between alterations in PMCA2 levels and neuronal injury was not well established. We now report that inhibition of PMCA activity in purified spinal cord neuronal cultures delays calcium clearance, increases the number of nonphosphorylated neurofilament H (SMI-32) immunoreactive cells, and induces swelling and beading of SMI-32-positive neurites. These changes are followed by activation of caspase-3 and neuronal loss. Importantly, the number of spinal cord motor neurons is significantly decreased in PMCA2-deficient mice and the deafwaddler 2J , a mouse with a functionally null mutation in the PMCA2 gene. Our findings suggest that a reduction in PMCA2 level or activity leading to delays in calcium clearance may cause neuronal damage and loss in the spinal cord.Keywords autoimmune disease; ATP2B2; excitotoxicity; cytoskeleton Neuronal and axonal dysfunction and loss have increasingly received attention as important contributors to neural decline in various central nervous system (CNS) disorders, including MS and spinal cord trauma. MS is a CNS disease that may initially show a relapsing-remitting course but finally leads to permanent neurological impairment (1,2). Classically, demyelination of structurally intact axons was considered to be the main cause of clinical symptoms and neural deficits in MS. However, recent studies indicate that axonal dysfunction is already evident at the earliest clinical stages of MS, and axonal transection or loss may be the cause of persistent, irreversible disability at later phases of the disease when remissions no longer occur (3-5).

Role of plasma membrane calcium ATPase 2 in spinal cord pathology

“…Inhibition of all PMCA activity by addition of 5(6)-carboxyeosin to pure neuronal cultures leads to cell death. This is preceded by a delay in the clearance of depolarization-induced calcium transients, neuritic damage and induction of activated caspase-3 [3] . These studies also indicated that most spinal cord neurons are dependent on PMCA activity for the effective clearance of depolarization-induced calcium transients, in vitro.…”

“…However, the activity of PMCAs can be modulated by a number of factors including calmodulin, phosphorylation by kinases, the protease calpain and caspases 1 and 3 [16] . The studies of Kurnellas et al [3] indicate that PMCAs are essential not only for the maintenance of basal calcium levels but also for the clearance of elevated intracellular calcium after stimulation or depolarization of spinal cord neurons. Other investigators have also reported that PMCAs contribute significantly to the removal of calcium from different neuronal subtypes in the retina and the dorsal root ganglia [17][18][19][20][21] .…”

“…In particular, investigations have shown that PMCA isoform 2 might be essential for the function and survival of spinal cord neurons, especially motor neurons [3,4] . The goal of this article is to summarize the major conceptual findings of studies that highlight the importance of PMCA2 in the spinal cord and to discuss the potential involvement of this calcium pump in neuronal degeneration in animal models of multiple sclerosis and spinal cord injury.…”

Optimized proteomic analysis of a mouse model of cerebellar dysfunction using amine-specific isobaric tags

“…PMCA2 −/− and PMCA2 +/+ mice were described previously [26]. For method optimization, normal C57BL/6 mice were used.…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…(11) Other oxidants inactivate the plasma membrane calcium-ATPase, leading to increased levels of intracellular calcium [44][45][46][47][48]; such inactivation of the calcium ATPase has substantial pathophysiological effects [45][46][47][48] and may well contribute to the prolonged impairment of calcium extrusion seen under circumstances, where the NO/ONOO − cycle may have a role [49][50][51].…”