title: Are PrP(C)s involved in some human myelin diseases? Relating experimental studies to human pathology.
abstract: We have experimentally demonstrated that cobalamin (Cbl) deficiency increases normal cellular prion (PrP(C)) levels in rat spinal cord (SC) and cerebrospinal fluid (CSF), and decreases PrP(C)-mRNA levels in rat SC. Repeated intracerebroventricular administrations of anti-octapeptide repeat-PrP(C)-region antibodies to Cbl-deficient (Cbl-D) rats prevent SC myelin lesions, and the administrations of PrP(C)s to otherwise normal rats cause SC white matter lesions similar to those induced by Cbl deficiency. Cbl positively regulates SC PrP(C) synthesis in rat by stimulating the local synthesis of epidermal growth factor (EGF), which also induces the local synthesis of PrP(C)-mRNAs, and downregulating the local synthesis of tumor necrosis factor(TNF)-α, thus preventing local PrP(C) overproduction. We have clinically demonstrated that PrP(C) levels are increased in the CSF of patients with subacute combined degeneration (SCD), unchanged in the CSF of patients with Alzheimer's disease and amyotrophic lateral sclerosis, and decreased in the CSF and SC of patients with multiple sclerosis (MS), regardless of its clinical course. We conclude that SCD (human and experimental) is a neurological disease due to excess PrP(C) without conformational change and aggregation, that the increase in PrP(C) levels in SCD and Cbl-D polyneuropathy and their decrease in MS CNS make them antipodian myelin diseases in terms of quantitative PrP(C) abnormalities, and that these abnormalities are related to myelin damage in the former, and impede myelin repair in the latter.
authors.affiliation: Department of Biomedical Sciences, Laboratory of Neuropathology, University of Milan, Via Mangiagalli 31, 20133 Milano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Veber
authors.affiliation: Department of Biomedical Sciences, Laboratory of Neuropathology, University of Milan, Via Mangiagalli 31, 20133 Milano, Italy. Electronic address: giuseppe.scalabrino@unimi.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scalabrino
mesh_terms: D000818:Animals; D006801:Humans; D056784:Leukoencephalopathies / Q000150:complications / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000473:pathology*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D052879:Subacute Combined Degeneration / Q000209:etiology; D014805:Vitamin B 12 / Q000235:genetics / Q000378:metabolism; D014806:Vitamin B 12 Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology
chemical_list: D018621:PrPC Proteins; D014805:Vitamin B 12
keywords: Cobalamin; Epidermal growth factor; Multiple sclerosis; Normal cellular prions; Subacute combined degeneration; Tumor necrosis factor-α