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Glycoform-Selective Prions in Sporadic and Genetic Variably Protease-Sensitive Prionopathies

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Prions and Diseases

Abstract

Unlike other human prion diseases, including the most common Creutzfeldt–Jakob disease (CJD), variably protease-sensitive prionopathy (VPSPr) is characterized by the deposition of a unique glycoform-selective pathogenic prion protein (PrPSc) in the brain. The proteinase K (PK) sensitivity of PrPSc from VPSPr is highly variable and appears to be mediated by PrP-129 polymorphisms. Its PK-resistant PrPSc (PrPres) consists of a pathognostic ladder-like electrophoretic gel profile consisting of two sets of multiple N- and C-terminally truncated fragments. Formation of this distinctive PrPSc is glycoform-selective, by which only two out of four normal PrP glycoforms (PrPC) convert to PrPSc. Strikingly, all the PrPSc features of sporadic VPSPr are shared by a genetic prion disease linked to the valine to isoleucine mutation at residue 180 of PrP (PrPV180I), previously defined as atypical genetic CJD. This chapter highlights the features of VPSPr PrPSc and provides evidence supporting the hypothesis that the condition with PrPV180I is the first genetic form of VPSPr.

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Acknowledgments

The authors want to thank Mohammed Moudjon for kindly providing the V14 and B209 antibodies. This work was supported in parts by the Michael J. Fox Foundation for Parkinson’s Research, the Alzheimer’s Association, Alzheimer’s Research UK, the Weston Brain Institute, the CJD Foundation to W.Q.Z, the National Institutes of Health (NIH) NS109532 and NS112010 to W.Q.Z. and Z.W. as well as NIH AG067607 to Z.W.

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The authors declare no conflict of interest.

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  1. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Zerui Wang, Jue Yuan, Tricia Gilliland, Maria Gerasimenko & Syed Zahid Ali Shah

  2. Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio, USA

    Wen-Quan Zou

  3. Institute of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China

    Wen-Quan Zou

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  1. Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, National Center for Regenerative Medicine Case Western Reserve University, School of Medicine, Cleveland, OH, USA

    Wen-Quan Zou

  2. Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Pierluigi Gambetti

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Wang, Z., Yuan, J., Gilliland, T., Gerasimenko, M., Shah, S.Z.A., Zou, WQ. (2023). Glycoform-Selective Prions in Sporadic and Genetic Variably Protease-Sensitive Prionopathies. In: Zou, WQ., Gambetti, P. (eds) Prions and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-031-20565-1_20

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