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Prions: generation and spread versus neurotoxicity.

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.
AuthorsMark Halliday, Helois Radford, Giovanna R Mallucci
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 29 Pg. 19862-8 (Jul 18 2014) ISSN: 1083-351X [Electronic] United States
PMID24860100 (Publication Type: Journal Article, Review)
Copyright© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • 7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
  • Amyloid beta-Peptides
  • Indoles
  • Prions
  • Protein Kinase Inhibitors
  • alpha-Synuclein
  • tau Proteins
  • PERK kinase
  • eIF-2 Kinase
  • Adenine
Topics
  • Adenine (analogs & derivatives, pharmacology)
  • Alzheimer Disease (etiology, metabolism)
  • Amyloid beta-Peptides (chemistry, metabolism)
  • Animals
  • Humans
  • Indoles (pharmacology)
  • Neurodegenerative Diseases (etiology, metabolism)
  • Parkinson Disease (etiology, metabolism)
  • Prion Diseases (drug therapy, etiology, metabolism)
  • Prions (chemistry, metabolism)
  • Protein Conformation
  • Protein Kinase Inhibitors (pharmacology)
  • Tauopathies (etiology, metabolism)
  • Unfolded Protein Response
  • alpha-Synuclein (chemistry, metabolism)
  • eIF-2 Kinase (antagonists & inhibitors, metabolism)
  • tau Proteins (chemistry, metabolism)

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