Normal prions as a new target of cobalamin deficiency in rat CNS

It is known that cobalamin (Cbl) deficiency damages myelin by increasing tumour necrosis factor(TNF)-α and decreasing epidermal growth factor(EGF) levels in rat central (CNS) and peripheral nervous system (PNS), and that TNF-α and EGF regulate normal prion protein (PrPC) expression. We investigated whether: a) the octapeptide repeat (OR)-region of PrPC (which is claimed to be myelinotrophic) is involved in the pathogenesis of rat Cbl-deficient (Cbl-D) neuropathy; and b) Cbl deficiency modifies PrPC levels of spinal cord (SC) and PNS in the rat. We intracerebroventricularly administered antibodies against the OR-region (OR-Abs) to Cbl-D rats to prevent SC and PNS myelin damage and maximum nerve conduction velocity (MNCV) abnormalities, and PrPCs to otherwise normal (ON) rats to reproduce Cbl-D-like lesions. The OR-Abs (but not when inactivated) normalized myelin ultrastructure and TNF-α levels in the SC and peripheral nerves, and MNCV values of Cbl-D rats. PrPC levels had increased in SC and peripheral nerves of Cbl-D rats by the time myelin lesions appeared. These increases were mediated by excess TNF-α. There were no changes in hepatic PrPC levels of Cbl-D rats. Cbl deficiency greatly reduced SC PrPC-mRNA levels, which were subsequently increased by Cbl and EGF, which proved to be effective in preventing the typical Cbl-D lesions. The SC and PNS of ON-, PrPC-treated rats showed typical Cbl-D lesions, significantly increased TNF-α levels, and significantly decreased MNCV values. Therefore: a) the number of OR regions in rat CNS and PNS seem to be “buffered” by Cbl; b) Cbl deficiency causes a vicious circle between TNF-α and PrPCs in rat CNS and PNS; and c) new PrPC synthesis is a common effect of different myelinotrophic agents in rat SC.