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J Biol Chem. 2014 Jul 18;289(29):19862-8. doi: 10.1074/jbc.R114.568477. Epub 2014 May 23.

Prions: generation and spread versus neurotoxicity.

Author information

1
From the Medical Research Council (MRC) Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, United Kingdom.
2
From the Medical Research Council (MRC) Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, United Kingdom grm7@le.ac.uk.

Abstract

Neurodegenerative diseases are characterized by the aggregation of misfolded proteins in the brain. Among these disorders are the prion diseases, which are transmissible, and in which the misfolded proteins ("prions") are also the infectious agent. Increasingly, it appears that misfolded proteins in Alzheimer and Parkinson diseases and the tauopathies also propagate in a "prion-like" manner. However, the association between prion formation, spread, and neurotoxicity is not clear. Recently, we showed that in prion disease, protein misfolding leads to neurodegeneration through dysregulation of generic proteostatic mechanisms, specifically, the unfolded protein response. Genetic and pharmacological manipulation of the unfolded protein response was neuroprotective despite continuing prion replication, hence dissociating this from neurotoxicity. The data have clear implications for treatment across the spectrum of these disorders, targeting pathogenic processes downstream of protein misfolding.

KEYWORDS:

Alzheimer Disease; Alzheimer's; Gene Therapy; Neurodegeneration; Neuroprotection; Prion; Unfolded Protein Response (UPR)

PMID:
24860100
PMCID:
PMC4106307
DOI:
10.1074/jbc.R114.568477
[Indexed for MEDLINE]
Free PMC Article

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