Myelin damage due to local quantitative abnormalities in normal prion levels: evidence from subacute combined degeneration and multiple sclerosis

Cobalamin (Cbl) deficiency causes an imbalance in some cytokines and growth factors in the central nervous system and peripheral nervous system (PNS) of the rat, and in the serum and cerebrospinal fluid (CSF) of adult Cbl-deficient (Cbl-D) patients. It is conceivable that this imbalance triggers subsequent cellular events. We hypothesized that an imbalance in normal prion (PrPC) levels and/or synthesis might be involved in the pathogenesis of Cbl-D neuropathy, and demonstrated that: (1) Cbl deficiency induces excess PrPC in rat spinal cord (SC) and PNS, concomitantly with myelin damage and PNS electrophysiological abnormalities; (2) the SC increase is mediated by a local Cbl deficiency-induced excess of tumor necrosis factor-α; (3) myelinotrophic Cbl and epidermal growth factor upregulate PrPC-mRNA levels in rat SC; (4) treatment with anti-PrPC octapeptide repeat region antibodies normalizes the ultrastructure of the Cbl-D rat SC and PNS myelins, and the PNS electrophysiological abnormalities, without modifying their Cbl-D status; (5) PrPC administration to otherwise normal rats causes SC and PNS myelin lesions and PNS electrophysiological abnormalities, similar to those of Cbl-D neuropathy; (6) CSF and serum PrPC concentrations in Cbl-D patients are significantly higher than in controls; and (7) these concentrations significantly correlate with their CSF and serum Cbl concentrations. CSF PrPC concentrations are significantly lower in patients with multiple sclerosis (MS) than neurological controls, but serum PrPC concentrations in patients with non-Cbl-D anemias and CSF PrPC concentrations in patients with non-myelin-damaging neurological diseases are normal.