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J Neurochem. 2016 Oct;139(2):162-180. doi: 10.1111/jnc.13772. Epub 2016 Sep 15.

Pathogenic mechanisms of prion protein, amyloid-β and α-synuclein misfolding: the prion concept and neurotoxicity of protein oligomers.

Author information

1
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia.
2
Howard Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.
3
Department of Pathology, University of Melbourne, Parkville, Vic., Australia.
4
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Vic., Australia.
5
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia. andrew.hill@latrobe.edu.au.
6
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Vic., Australia. andrew.hill@latrobe.edu.au.

Abstract

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 PrPSc ; a misfolded isoform of the normal cellular protein, PrPC , which is found accumulated in the CNS in disease. Today, mounting evidence suggests other aggregating proteins, such as amyloid-β (Aβ) and α-synuclein (α-syn), proteins associated with Alzheimer's disease and synucleinopathies, respectively, share similar biophysical and biochemical properties with PrPSc 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 Aβ 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.

KEYWORDS:

Alzheimer's disease; amyloid-β; neurodegenerative diseases; prion; prion disease; synucleinopathies

PMID:
27529376
DOI:
10.1111/jnc.13772
[Indexed for MEDLINE]
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