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Insoluble Cellular Prion Protein and Other Neurodegeneration-Related Protein Aggregates in the Brain of Asymptomatic Individuals

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Prions and Diseases

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Abstract

The pathological detergent-insoluble prion protein (PrPSc) is derived from its normal detergent-soluble cellular form (PrPC) through a structural transition from α-helixes into β-sheets, which is associated with a group of transmissible neurodegenerative diseases or prion diseases. According to the prevailing seeding model, PrPSc formation requires a precursor of PrPSc or an intermediate form between PrPC and PrPSc. However, the precursor or intermediate form in the brain remains to be determined. In 2006, we identified in uninfected human and animal brains a novel PrP conformer termed insoluble PrPC (iPrPC) that possesses PrPSc-like properties such as detergent-insolubility, resistance to protease, and tendency to form aggregates. Notably, other common neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) have recently been proposed to share a prion-like seeding mechanism by which the detergent-soluble brain monomeric cellular proteins form the detergent-insoluble misfolded protein aggregates that transmit from cells to cells. This chapter reviews the physiochemical properties of iPrPC and discusses its formation and pathophysiology. It also highlights the findings and implications of other misfolded proteins such as amyloid-β, tau, and α-synuclein associated with AD and PD in the brain of asymptomatic individuals.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) grant NS112010, NIH NS109532, the BAND grant jointly funded by the Alzheimer’s Association, Alzheimer’s Research, UK, Michael J. Fox Foundation for Parkinson’s Research (MJFF), and Weston Brain Institute, α-synuclein seed amplification grant supported by MJFF, and the CJD Foundation grant.

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

    Wen-Quan Zou

  2. 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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Zou, WQ. (2023). Insoluble Cellular Prion Protein and Other Neurodegeneration-Related Protein Aggregates in the Brain of Asymptomatic Individuals. In: Zou, WQ., Gambetti, P. (eds) Prions and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-031-20565-1_4

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