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Cited by 92Prion Diseases and Protein MisfoldingAlzheimer's disease research and treatmentsParkinson's Disease Mechanisms and Treatments

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

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Ugalde, Cathryn L., Finkelstein, David I., Lawson, Victoria A., Hill, Andrew F.·2016·Journal of Neurochemistry
DOI 10.1111/jnc.13772
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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 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. image 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.

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  • Microglia play a fundamental role in the demise of the neuronal population in several neurodegenerative diseases.

    “Since microglia play a fundamental role in the demise of the neuronal population in several neurodegenerative diseases, we tested whether Tet2 expression could also be affected by different pathological protein aggregates seen in a number of neurodegenerative diseases typically associated to neuroinflammation (Ugalde et al., 2016).”

    From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Ugalde et al., 2016

    The “Neurotoxicity of misfolded protein” section describes neuronal damage and loss across proteinopathies, and an Author Manuscript passage mentions microgliosis alongside disease in a mouse model. Neither says that microglia play a fundamental role in causing neuronal loss. Searches for microglia and neuroinflammation found no passage establishing that attributed role; page numbers were unavailable in our copy. (LLM, conf=0.76)

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Authors
Ugalde, C. L., Finkelstein, D. I., Lawson, V. A., & Hill, A. F.
Affiliations
  • The University of Melbourne (AU)
  • Florey Institute of Neuroscience and Mental Health (AU)
Corresponding author
Hill, Andrew F.
ORCID
Venue
Journal of Neurochemistry
Publisher
Wiley
Published
2016-09-15
Volume
139
Issue
2
Pages
162-180
ISSN
  • 0022-3042 (ISSN-L)
  • 1471-4159
DOI
10.1111/jnc.13772
OpenAlex
W2512250682
Cited by
92
References
22
Citations by year
2026: 3 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 17 · 2020: 10 · 2019: 12 · 2018: 13 · 2017: 13 · 2016: 2
FWCI
1.21
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Journal of Neurochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Victoria University Research Repository (Victoria University) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
Funders
National Health and Medical Research Council (628946)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
prion disease, prion protein, PrPSc, amyloid-beta, alpha-synuclein, protein misfolding, protein aggregation, protein oligomers, neurotoxicity, Alzheimer's disease, Parkinson's disease, synucleinopathies, proteinopathies, neurodegenerative diseases
MeSH terms
Prion Proteins, Alzheimer Disease, Animals, Humans, Amyloid beta-Peptides, Prion Diseases, PrPSc Proteins, alpha-Synuclein, Proteostasis Deficiencies

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