Distribution of a calcium channel subunit in dystrophic axons in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are immune-mediated diseases of the CNS. They are characterized by widespread i nflammation, demyelination and a variable degree of axonal loss. Recent mag netic resonance spectroscopy studies have indicated that axonal damage and loss are a reliable correlate of permanent clinical disability. Accordingly , neuropathological studies have confirmed the presence and timing of axona l injury in multiple sclerosis lesions. The mechanisms of axonal degenerati on, however, are unclear. Since calcium influx may mediate axonal damage, w e have studied the distribution of the pore-forming subunit of neuronal (N) type voltage-gated calcium channels in the lesions of multiple sclerosis an d EAE. We found that alpha (1B), the pore-forming subunit of N-type calcium channels, was accumulated within axons and axonal spheroids of actively de myelinating lesions. The axonal staining pattern of alpha (1B) was comparab le with that of beta -amyloid precursor protein, which is an early and sens itive marker for disturbance of axonal transport. Importantly, within these injured axons, alpha (1B) was not only accumulated, but also integrated in the axoplasmic membrane, as shown by immune electron microscopy on the EAE material. This ectopic distribution of calcium channels in the axonal memb rane may result in increased calcium influx, contributing to axonal degener ation, possibly via the activation of neutral proteases. Our data suggest t hat calcium influx through voltage-dependent calcium channels is one possib le candidate mechanism for axonal degeneration in inflammatory demyelinatin g disorders.