Intrinsic toxicity of the cellular prion protein is regulated by its conserved central region

Roseman, Graham; Wu, Bo; Wadolkowski, Mark A.; Millhauser, Glenn L.

doi:10.1096/fj.201902749rr

Cited by 3 publications

(1 citation statement)

References 73 publications

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“…Prions are comprised of PrP Sc , the self-templating, disease-specific conformation of the host-encoded prion protein, PrP C [8,9,10,11]. PrP C is a glycosylphosphatidylinositol anchored cell surface protein with two N-linked glycosylation sites that is required for prion conversion and neurotoxicity [12,13,14,15,16,17]. Prion conversion occurs at the cell surface and/or in the endosomal lysosomal system resulting in a complete restructuring of PrP C from a monomeric alpha helical structure to that of fibrillar parallel in-register intermolecular β-sheet (PIRIBS) structure [18,19,20,21].…”

Section: Introductionmentioning

confidence: 99%

Evidence for preexisting prion substrain diversity in a biologically cloned prion strain

Gunnels,

Shikiya,

York

et al. 2023

PLoS Pathog

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Prion diseases are a group of inevitably fatal neurodegenerative disorders affecting numerous mammalian species, including Sapiens. Prions are composed of PrPSc, the disease specific conformation of the host encoded prion protein. Prion strains are operationally defined as a heritable phenotype of disease under controlled transmission conditions. Treatment of rodents with anti-prion drugs results in the emergence of drug-resistant prion strains and suggest that prion strains are comprised of a dominant strain and substrains. While much experimental evidence is consistent with this hypothesis, direct observation of substrains has not been observed. Here we show that replication of the dominant strain is required for suppression of a substrain. Based on this observation we reasoned that selective reduction of the dominant strain may allow for emergence of substrains. Using a combination of biochemical methods to selectively reduce drowsy (DY) PrPSc from biologically-cloned DY transmissible mink encephalopathy (TME)-infected brain resulted in the emergence of strains with different properties than DY TME. The selection methods did not occur during prion formation, suggesting the substrains identified preexisted in the DY TME-infected brain. We show that DY TME is biologically stable, even under conditions of serial passage at high titer that can lead to strain breakdown. Substrains therefore can exist under conditions where the dominant strain does not allow for substrain emergence suggesting that substrains are a common feature of prions. This observation has mechanistic implications for prion strain evolution, drug resistance and interspecies transmission.

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Section: Introductionmentioning

confidence: 99%

Evidence for preexisting prion substrain diversity in a biologically cloned prion strain

Gunnels,

Shikiya,

York

et al. 2023

PLoS Pathog

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Multisite interactions of prions with membranes and native nanodiscs

Overduin

Wille

Westaway

2021

Chemistry and Physics of Lipids

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The importance of prion research

Eid,

Lee,

Verkuyl

et al. 2024

Biochem. Cell Biol.

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Over the past four decades, prion diseases have received considerable research attention owing to their potential to be transmitted within and across species as well as their consequences for human and animal health. The unprecedented nature of prions has led to the discovery of a paradigm of templated protein misfolding that underlies a diverse range of both disease-related and normal biological processes. Indeed, the “prion-like” misfolding and propagation of protein aggregates is now recognized as a common underlying disease mechanism in human neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease and the prion principle has led to the development of novel diagnostic and therapeutic strategies for these illnesses. Despite these advances, research into the fundamental biology of prion diseases has declined, likely due to their rarity and the absence of an acute human health crisis. Given the past translational influence, continued research on the etiology, pathogenesis, and transmission of prion disease should remain a priority. In this review we highlight several important “unsolved mysteries” in the prion disease research field and how solving them may be crucial for the development of effective therapeutics, preventing future outbreaks of prion disease, and understanding the pathobiology of more common human neurodegenerative disorders.

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Intrinsic toxicity of the cellular prion protein is regulated by its conserved central region

Cited by 3 publications

References 73 publications

Evidence for preexisting prion substrain diversity in a biologically cloned prion strain

Evidence for preexisting prion substrain diversity in a biologically cloned prion strain

Multisite interactions of prions with membranes and native nanodiscs

The importance of prion research

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