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Molecular Mechanisms Encoding Quantitative and Qualitative Traits of Prion Strains

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Prions and Diseases

Abstract

Yeast, fungal, and mammalian prions determine heritable as well as infectious traits. In mammals, prions cause a group of fatal and rapidly progressive neurodegenerative diseases, originally described as transmissible spongiform encephalopathies (TSEs). Variations in prions, which cause different disease phenotypes, are referred to as strains. Mammalian prion strains are differentiated by qualitative characteristics such as clinical symptoms, brain pathology, targeted brain anatomical areas and cells, or Western blot patterns of glycosylated or deglycosylated pathogenic prion protein (PrPSc). Quantitative prion traits are determined by incubation time, prion dose response, proteolytic sensitivity, and conformational stability of PrPSc. The high degree of fidelity with which prion strains replicate requires a precise molecular mechanism that can account for all these characteristics. Remarkable progress in the past decade produced many lines of evidence arguing that prion traits are encoded in the self-replicating conformation of PrPSc that is unique for each strain. Thus, prions behave like proteinaceous genes. The determination of the full spectrum of human and animal prion strains and the conformational features in the pathogenic human prion protein that govern replication of prion strains is essential for the development of diagnostic as well as therapeutic strategies.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

CDI:

Conformation-dependent immunoassay

CHO:

N-linked complex glycosylation chains

CJD:

Creutzfeldt–Jakob disease

CPA:

Cell panel assay

ER:

Endoplasmic reticulum

FFI:

Fatal familial insomnia

GSS:

Gerstmann–Sträussler–Scheinker syndrome

PMCA:

Protein misfolding cyclic amplification

PRNP:

Prion protein gene

PrP:

Prion protein

PrPC :

Normal or cellular prion protein

PrPSc :

Pathogenic prion protein

rPrPSc :

Protease-resistant conformers of pathogenic prion protein (PrP 27-30)

sCJD:

Sporadic Creutzfeldt–Jakob disease

SFI:

Sporadic fatal insomnia

sPrPSc :

Protease-sensitive conformers of pathogenic prion protein

SSCA:

Standard scrapie cell assay

TSE:

Transmissible spongiform encephalopathy

VPSPr:

Variable protease-sensitive prionopathy

WB:

Western blot

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Acknowledgments

This work was supported by grants from NIA (AG-14359), NINDS (NS074317), CDC (UR8/CCU515004), and the Charles S. Britton Fund.

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  1. Department of Pathology and Department of Neurology, National Prion Disease Surveillance Center, School of Medicine, Case Western Reserve University, 2085 Adelbert Rd, Cleveland, OH, 44106, USA

    Jiri G. Safar M.D.

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  1. Jiri G. Safar M.D.
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Correspondence to Jiri G. Safar M.D. .

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  1. , Department of Pathology, Case Western Reserve University School o, 2085 Adelbert Road, Cleveland, 44106, Ohio, USA

    Wen-Quan Zou

  2. , Department of Neuropathology, Case Western Reserve University School o, 2085 Adelbert Road, Cleveland, 44106, Ohio, USA

    Pierluigi Gambetti

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Safar, J.G. (2013). Molecular Mechanisms Encoding Quantitative and Qualitative Traits of Prion Strains. In: Zou, WQ., Gambetti, P. (eds) Prions and Diseases. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5305-5_12

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