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Pathogenic mechanisms of prion protein, amyloid‐β and α‐synuclein misfolding: the prion concept and neurotoxicity of protein oligomers
Author(s) -
Ugalde Cathryn L.,
Finkelstein David I.,
Lawson Victoria A.,
Hill Andrew F.
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13772
Subject(s) - synucleinopathies , neurotoxicity , biology , alpha synuclein , amyloid (mycology) , neurodegeneration , protein folding , protein aggregation , prion protein , gene isoform , disease , parkinson's disease , microbiology and biotechnology , chemistry , biochemistry , medicine , pathology , gene , toxicity , botany , organic chemistry
Proteinopathies represent a group of diseases characterized by the unregulated misfolding and aggregation of proteins. Accumulation of misfolded protein in the central nervous system (CNS) is associated with neurodegenerative diseases, such as the transmissible spongiform encephalopathies (or prion diseases), Alzheimer's disease, and the synucleinopathies (the most common of which is Parkinson's disease). Of these, the pathogenic mechanisms of prion diseases are particularly striking where the transmissible, causative agent of disease is the prion, or proteinaceous infectious particle . Prions are composed almost exclusively of PrP Sc ; a misfolded isoform of the normal cellular protein, PrP C , which is found accumulated in the CNS in disease. Today, mounting evidence suggests other aggregating proteins, such as amyloid‐β (A β ) and α ‐synuclein (α‐syn), proteins associated with Alzheimer's disease and synucleinopathies, respectively, share similar biophysical and biochemical properties with PrP Sc that influences how they misfold, aggregate, and propagate in disease. In this regard, the definition of a ‘prion’ may ultimately expand to include other pathogenic proteins. Unifying knowledge of folded proteins may also reveal common mechanisms associated with other features of disease that are less understood, such as neurotoxicity. This review discusses the common features A β and α ‐syn share with PrP and neurotoxic mechanisms associated with these misfolded proteins.Several proteins are known to misfold and accumulate in the central nervous system causing a range of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and the prion diseases. Prions are transmissible misfolded conformers of the prion protein, PrP, which seed further generation of infectious proteins. Similar effects have recently been observed in proteins associated with Alzheimer's disease and the synucleinopathies, leading to the proposition that the definition of a ‘prion’ may ultimately expand to include other pathogenic proteins. Unifying knowledge of misfolded proteins may also reveal common mechanisms associated with other features of disease that are less understood, such as neurotoxicity.