title: 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.
authors.affiliation: From the Medical Research Council (MRC) Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Halliday
authors.affiliation: From the Medical Research Council (MRC) Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Helois
authors.initials: H
authors.lastname: Radford
authors.affiliation: From the Medical Research Council (MRC) Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, United Kingdom grm7@le.ac.uk.
authors.forename: Giovanna R
authors.initials: GR
authors.lastname: Mallucci
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D024801:Tauopathies / Q000209:etiology / Q000378:metabolism; D056811:Unfolded Protein Response; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000225:Adenine; D016229:Amyloid beta-Peptides; D007211:Indoles; D011328:Prions; D047428:Protein Kinase Inhibitors; D051844:alpha-Synuclein; D019892:eIF-2 Kinase; D016875:tau Proteins; C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine
keywords: Alzheimer Disease; Alzheimer's; Gene Therapy; Neurodegeneration; Neuroprotection; Prion; Unfolded Protein Response (UPR)