Relationships between cobalamin, epidermal growth factor, and normal prions in the myelin maintenance of central nervous system

Abstract

Cobalamin (Cbl), epidermal growth factor (EGF), and prions (PrPs) are key molecules for myelin maintenance in the central and peripheral nervous systems. Cbl and EGF increase normal prion (PrPC) synthesis and PrPC levels in rat spinal cord (SC) and elsewhere. Cbl deficiency increases PrPC levels in rat SC and cerebrospinal fluid (CSF), and decreases PrPC-mRNA levels in rat SC. The administration of anti-octapeptide repeat PrPC region antibodies (Abs) to Cbl-deficient (Cbl-D) rats prevents SC myelin lesions and a local increase in tumor necrosis factor (TNF)-α levels, whereas anti-TNF-α Abs prevent SC myelin lesions and the increase in SC and CSF PrPC levels. As it is known that both Cbl and EGF regulate SC PrPC synthesis independently, and that Cbl regulates SC EGF synthesis, EGF may play both Cbl-independent and Cbl-dependent roles. When Cbl-D rats undergo Cbl replacement therapy, SC PrPC levels are similar to those observed in Cbl-D rats. In rat frontal cortex (which is marginally affected by Cbl deficiency in histological terms), Cbl deficiency decreases PrPC levels and the increase induced by Cbl replacement leads to their normalization. Increased nerve PrPC levels are detected in the myelin lesions of the peripheral neuropathy of Cbl-D rats, and CSF PrPC levels are also increased in Cbl-D patients (but not in patients with Cbl-unrelated neurological diseases). Various common steps in the downstream signaling pathway of Cbl, EGF, and PrPC underlines the close relationship between the three molecules in keeping myelin normal.