Cobalamin and normal prions: a new horizon for cobalamin neurotrophism.

It is known that cobalamin (Cbl) deficiency damages myelin by increasing tumor necrosis factor (TNF)-α and decreasing epidermal growth factor (EGF) levels in rat central nervous system (CNS), and affects the peripheral nervous system (PNS) morphologically and functionally. It is also known that some polyneuropathies not due to Cbl deficiency are connected with increased TNF-α levels, and that various cytokines (including TNF-α) and growth factors regulate the in vitro synthesis of normal prions (PrP(C)s). Given that there is extensive evidence that PrP(C)s play a key role in the maintenance of CNS and PNS myelin, we investigated whether the PrP(C) octapeptide repeat (OR) region is involved in the pathogenesis of rat Cbl-deficient (Cbl-D) polyneuropathy. After intracerebroventricularly administering antibodies (Abs) against the OR region (OR-Abs) to Cbl-D rats to prevent myelin damage and maximum nerve conduction velocity (MNCV) abnormalities, and PrP(C)s to otherwise normal rats to reproduce PNS Cbl-D-like lesions, we measured PrP(C) levels and MNCV of the sciatic and tibial nerves. PrP(C) and TNF-α levels were increased in sciatic and tibial nerves of Cbl-D and saline-treated rats, and the OR-Abs normalized the myelin ultrastructure, TNF-α levels, and MNCV values of the sciatic and tibial nerves of Cbl-D rats. The same peripheral nerves of the otherwise normal PrP(C)-treated rats showed typical Cbl-D myelin lesions, significantly increased TNF-α levels, and significantly decreased MNCV values. These findings demonstrate that Cbl deficiency induces excess PrP(C)s and thereby excess OR regions, which seem to be responsible for the PNS myelin damage, as has recently been found in the case of CNS myelin damage [66]. Furthermore, excess TNF-α is also involved in the pathogenesis of Cbl-D polyneuropathy. In conclusion, we have extended the list of prion diseases by adding one caused by excess PrP(C)s and the polyneuropathies related to excess TNF-α.