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The function of the cellular prion protein in health and disease

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Abstract

The essential role of the cellular prion protein (PrPC) in prion disorders such as Creutzfeldt–Jakob disease is well documented. Moreover, evidence is accumulating that PrPC may act as a receptor for protein aggregates and transduce neurotoxic signals in more common neurodegenerative disorders, such as Alzheimer’s disease. Although the pathological roles of PrPC have been thoroughly characterized, a general consensus on its physiological function within the brain has not yet been established. Knockout studies in various organisms, ranging from zebrafish to mice, have implicated PrPC in a diverse range of nervous system-related activities that include a key role in the maintenance of peripheral nerve myelination as well as a general ability to protect against neurotoxic stimuli. Thus, the function of PrPC may be multifaceted, with different cell types taking advantage of unique aspects of its biology. Deciphering the cellular function(s) of PrPC and the consequences of its absence is not simply an academic curiosity, since lowering PrPC levels in the brain is predicted to be a powerful therapeutic strategy for the treatment of prion disease. In this review, we outline the various approaches that have been employed in an effort to uncover the physiological and pathological functions of PrPC. While these studies have revealed important clues about the biology of the prion protein, the precise reason for PrPC’s existence remains enigmatic.

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Acknowledgements

The authors thank Gerold Schmitt-Ulms, Janice Robertson, and Zaid Al-Azzawi for critical reading of the manuscript. Research in the Watts lab is supported by grants from the Canadian Institutes of Health Research (CIHR), the Natural Science and Engineering Research Council of Canada (NSERC), the Canadian Foundation for Innovation (CFI), Alzheimer Society Canada, and Parkinson Canada.

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  1. Department of Biochemistry, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, Rm. 4KD481, 60 Leonard Ave., Toronto, ON, M5T 2S8, Canada

    Joel C. Watts, Matthew E. C. Bourkas & Hamza Arshad

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Watts, J.C., Bourkas, M.E.C. & Arshad, H. The function of the cellular prion protein in health and disease. Acta Neuropathol 135, 159–178 (2018). https://doi.org/10.1007/s00401-017-1790-y

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