Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury.
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.
Kurnellas
Michael P
MP
Neurology and Neuroscience, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA.
Nicot
Arnaud
A
Shull
Gary E
GE
Elkabes
Stella
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000172:deficiency*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency*; D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000378:metabolism; D009103:Multiple Sclerosis / Q000473:pathology*; D009410:Nerve Degeneration; D016501:Neurites / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology*; D053499:Plasma Membrane Calcium-Transporting ATPases; D051381:Rats; D013116:Spinal Cord / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000473:pathology*; D009435:Synaptic Transmission / Q000502:physiology
C506961:Atp2b2 protein, rat; D027682:Cation Transport Proteins; D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse; D000252:Calcium-Transporting ATPases; D002118:Calcium