Prion Protein Accumulation and Neuroprotection in Hypoxic Brain Damage

Abstract

The function of the normal conformational isoform of prion protein, PrP(C), remains unclear although lines of research have suggested a role in the cellular response to oxidative stress. Here we investigate the expression of PrP(C) in hypoxic brain tissues to examine whether PrP(C) is in part regulated by neuronal stress. Cases of adult cerebral ischemia and perinatal hypoxic-ischemic injury in humans were compared with control tissues. PrP(C) immunoreactivity accumulates within neuronal processes in the penumbra of hypoxic damage in adult brain, and within neuronal soma in cases of perinatal hypoxic-ischemic injury, and in situ hybridization analysis suggests an up-regulation of PrP mRNA during hypoxia. Rodents also showed an accumulation of PrP(C) in neuronal soma within the penumbra of ischemic lesions. Furthermore, the infarct size in PrP-null mice was significantly greater than in the wild type, supporting the proposed role for PrP(C) in the neuroprotective adaptive cellular response to hypoxic injury.

Disease‐associated prion protein is not detectable in human systemic amyloid deposits

“…If, in contrast to our present uniformly negative observations, PrP Sc or PrP res were to be detected in human amyloidotic tissues, extensive control studies with human tissues containing other, non-amyloid, pathologies would be essential to determine whether there was any specific relationship with amyloidosis, since over-expression of PrP may be a general response to tissue pathology. Indeed, we have previously reported that prion protein is present in the penumbra of brain infarcts, but this results from overexpression of PrP C rather than local accumulation of PrP Sc [38].…”

Identification of a Novel Endoplasmic Reticulum Stress Response Element Regulated by XBP1

“…In addition, polymorphisms in the regulatory region of PRNP may present a risk for Creutzfeldt-Jakob disease (6,7). Furthermore, accruing evidence implicates the normal cellular PrP in a number of essential cellular functions including neuroprotection against oxidative stress (8,9), copper toxicity (10), Bax-mediated cell death (11), and ischemia (12)(13)(14)(15). There is also evidence that PrP participates in normal synaptic function (16) and myelination (17,18).…”

Disease-associated Mutations in the Prion Protein Impair Laminin-induced Process Outgrowth and Survival

“…In the last decade a diverse range of functions has been attributed to the native PrP C protein, such as neuroprotection against cellular and systemic insults, neuritogenesis, neuronal plasticity and excitability, and memory formation and consolidation (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Noteworthy, PrP C mutations associated to CJD, fatal familial insomnia, and Gerstmann-Straussler-Scheinker disease decrease or abolish the anti-bax function in primary human neurons and breast cancer cell lines promoting programmed cell death (34).…”