Myelin damage due to local quantitative abnormalities in normal prion levels: evidence from subacute combined degeneration and multiple sclerosis

Abstract

Cobalamin (Cbl) deficiency causes an imbalance in some cytokines and growth factors in the central nervous system and peripheral nervous system (PNS) of the rat, and in the serum and cerebrospinal fluid (CSF) of adult Cbl-deficient (Cbl-D) patients. It is conceivable that this imbalance triggers subsequent cellular events. We hypothesized that an imbalance in normal prion (PrP(C)) levels and/or synthesis might be involved in the pathogenesis of Cbl-D neuropathy, and demonstrated that: (1) Cbl deficiency induces excess PrP(C) in rat spinal cord (SC) and PNS, concomitantly with myelin damage and PNS electrophysiological abnormalities; (2) the SC increase is mediated by a local Cbl deficiency-induced excess of tumor necrosis factor-α; (3) myelinotrophic Cbl and epidermal growth factor upregulate PrP(C)-mRNA levels in rat SC; (4) treatment with anti-PrP(C) octapeptide repeat region antibodies normalizes the ultrastructure of the Cbl-D rat SC and PNS myelins, and the PNS electrophysiological abnormalities, without modifying their Cbl-D status; (5) PrP(C) administration to otherwise normal rats causes SC and PNS myelin lesions and PNS electrophysiological abnormalities, similar to those of Cbl-D neuropathy; (6) CSF and serum PrP(C) concentrations in Cbl-D patients are significantly higher than in controls; and (7) these concentrations significantly correlate with their CSF and serum Cbl concentrations. CSF PrP(C) concentrations are significantly lower in patients with multiple sclerosis (MS) than neurological controls, but serum PrP(C) concentrations in patients with non-Cbl-D anemias and CSF PrP(C) concentrations in patients with non-myelin-damaging neurological diseases are normal.

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

“…** p < 0.05 vs. Cbl-D, saline-treated rats. levels contributed to the local increase in PrP C levels and vice versa (Scalabrino et al, 2012;Scalabrino and Veber, 2014). The quantitative SC and CSF PrP C abnormalities, myelin damage, increased SC and CSF TNF-␣ levels, and the electrophysiological PNS abnormalities are prevented when Cbl-D rats are treated with i.c.v.…”

“…In the case of Cbl deficiency, most PrP C s may be moved to the cytoplasm and then secreted into extracellular space and the main physiological fluids (i.e. blood and CSF) (Glatzel et al, 2005;Scalabrino and Veber, 2014), but, when Cbl-induced myelin repair occurs, new local PrP C synthesis is required.…”

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

“…Besides Cbl and epidermal growth factor, prions are also involved in myelin maintenance. Prion levels and synthesis are regulated by Cbl in concert with epidermal growth factor and Cbl deficiency may cause altered prion distribution mediated by TNFα activation.…”

Normal Cellular Prions: Friends and Foes towards Human CNS Myelin? The Role of Cobalamin

“…with subacute combined degeneration) than in neurological controls; ii) CSF PrPC levels correlated significantly with CSF Cbl levels, and iii) CSF PrPC levels were normal in the patients with amyotrophic lateral sclerosis or Alzheimer's disease. Instead, we found significantly decreased CSF PrPC levels in patients with multiple sclerosis (MS) (regardless of its clinical course) [3,4]. The PrPC levels of post-mortem SC samples of MS patients were also decreased.…”