Prion diseases and epidemics: genetic factors in a protein only disorder – Biologisk Institut - Københavns Universitet

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Prion diseases and epidemics: genetic factors in a protein only disorder

Speaker: Professor Simon Mead, MRC Prion Unit, University College London
Host: Assistant professor Ida Moltke, Computational and RNA Biology, BIO-UCPH

I will talk about the prion diseases, including descriptions of the epidemics of kuru in Papua New Guinea and variant Creutzfeldt-Jakob disease in the UK and the rest of Europe. I will review how prions were discovered and that the mechanisms of disease are becoming understood, involving the misfolding of a normal body protein into chain structures by seeded polymerisation. This protein-only mechanism allows for the inheritance of information encoded by the three dimensional structure of the abnormal protein, and is likely to be the basis of distinct "strains"

of prion disease. These mechanisms are proving to be increasingly relevant to other neurodegenerative diseases. One aspect of my research has focused on genetic factors: by studying the tail-end of the kuru epidemic, particularly elderly women who participated in cannibalistic mortuary feasts, we found an amino acid variant of the prion protein gene that was selected for and appears to confer resistance to kuru in the population and in transgenic mice. Finally I will talk about experimental treatments and how "evolution" of the prion pathogen in patients could be a problem for some treatment strategies.

Selected papers
Mead S, Whitfield J, Poulter M, Shah P, Uphill J, Campbell T, Al-Doujaily H, Hummerich H, Beck J, Mein C, Verzilli C, Whittaker J, Alpers M, Collinge J A novel protective prion protein variant co-localises with kuru exposure. N Engl J Med 2009;361:2056–65

Mead S, Poulter M, Uphill J, Beck J, Whitfield J, Webb TE, Campbell T, Adamson G, Deriziotis P, Tabrizi SJ, Hummerich H, Verzilli C, Alpers MP, Whittaker JC, Collinge J Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study. Lancet Neurol 2009;8(1):57-66.

Mead S, Stumpf MP, Whitfield J, Beck J, Poulter M, Campbell T, Uphill J, Goldstein D, Alpers MP, Fisher E, Collinge J. Balancing selection at the prion protein gene consistent with prehistoric kuru-like epidemics.
Science 2003; 300: 640-3.

Webb TE, Poulter M, Beck J, Uphill J, Adamson G, Campbell T, Linehan J, Powell C, Brandner S, Pal S, Siddique D, Wadsworth JD, Joiner S, Alner K, Petersen C, Hampson S, Rhymes C, Treacy C, Storey E, Geschwind MD, Nemeth AH, Wroe S, Collinge J, Mead S Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.
Brain 2008;131(10):2632-46.