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Cited by 51Prion Diseases and Protein MisfoldingAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

How an Infection of Sheep Revealed Prion Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders

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Carlson, George A., Prusiner, Stanley B.·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22094861PMC PMC8125442
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Abstract

Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived Aβ peptides, tau, and α-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field.

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  • Unlike infectious prion diseases, intercellular spread of injected pathological TDP-43 has not been found to be sufficient to drive neurodegenerative effects leading to death of recipient cells or to neurological decline.

    “But unlike infectious prion diseases (Carlson & Prusiner 2021), intercellular spread of injected pathological TDP-43 has not been found to be sufficient to drive neurodegenerative effects leading to death of recipient cells or to neurological decline.”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Carlson & Prusiner 2021

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Sorted by citations

Authors
Carlson, G. A., & Prusiner, S. B.
Affiliations
University of California, San Francisco (US)
Corresponding author
Prusiner, Stanley B.
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-05-04
Volume
22
Issue
9
Pages
4861
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms22094861
PMC
PMC8125442
OpenAlex
W3159710340
Cited by
51
References
13
Citations by year
2026: 4 · 2025: 10 · 2024: 8 · 2023: 8 · 2022: 16 · 2021: 5
FWCI
1.00
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (AB002132)
  • Brockman Foundation (NA)
  • Sherman Fairchild Foundation (NA)
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 › Amyotrophic Lateral Sclerosis Research
Keywords
prion hypothesis, prion protein, scrapie, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, protein misfolding, protein aggregation, prion replication, familial prion disease, amyloid-beta, tau protein, alpha-synuclein, neurodegenerative diseases
MeSH terms
Prion Proteins, Alzheimer Disease, Animals, Humans, Creutzfeldt-Jakob Syndrome, Mutation, Parkinson Disease, Prions, Scrapie, Sheep, Gene Expression, Gerstmann-Straussler-Scheinker Disease, Amyloid beta-Peptides, tau Proteins, Protein Folding, Mice, alpha-Synuclein, Frontotemporal Dementia

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