title: Normal prions as a new target of cobalamin (vitamin B12) in rat central nervous system.
abstract: The pathogenesis of cobalamin (Cbl)-deficient (Cbl-D) neuropathy and the role of normal prions (PrPcs) in myelin maintenance are both subjects of debate. We have demonstrated that Cbl deficiency damages myelin by increasing tumor necrosis factor (TNF)-α, and decreasing epidermal growth factor (EGF) levels in the rat central nervous system (CNS). It is known that TNF-α and EGF regulate PrPc expression in vitro, and that myelin vacuolation, reactive astrocytosis and microglial activation are common to rat Cbl-D neuropathy and some prion diseases. We have shown that Cbl deficiency leads to high levels of PrPcs [particularly the octapeptide repeat (OR) domains] in the rat CNS thereby damaging the spinal cord (SC) myelin, and that chronic intra-cerebroventricular treatment with anti-OR antibodies normalizes SC myelin morphology. We have also found that PrPc levels are increased in the SC of Cbl-D rats by the time the myelin lesions appear, and that this increase is mediated by excess myelinotoxic TNF-α and prevented by EGF treatment, which has proved to be as effective as Cbl in preventing Cbl deficiency-induced lesions. Cbl stimulates PrPc mRNA-related synthesis in Cbl-D SC and duodenum, two rat tissues that are severely affected by Cbl deficiency. New PrPc synthesis is a common effect of various myelinotrophic agents, two of which (EGF and anti-TNF-α antibodies) also stimulate PrPc mRNA-related synthesis in the SC of Cbl-D rats.
authors.affiliation: Laboratory of Neuropathology, Città Studi Department, University of Milan,Milan, Italy. giuseppe.scalabrino@unimi.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scalabrino
authors.forename: Daniela
authors.initials: D
authors.lastname: Veber
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D003300:Copper / Q000134:cerebrospinal fluid; D004815:Epidermal Growth Factor / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014805:Vitamin B 12 / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000378:metabolism / Q000473:pathology
chemical_list: D011328:Prions; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D003300:Copper; D014805:Vitamin B 12