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Prof Simon Mead
G01
Institute of Prion Diseases
Cleveland St
London
WC1N 3BG
Prof Simon Mead profile picture
Appointment
  • clinical professor
  • MRC Prion Unit at UCL
  • UCL Institute of Prion Diseases
  • Faculty of Brain Sciences
Biography

After medical training at Cambridge and Oxford Universities and a PhD in the genetics of prion diseases at Imperial College London, Simon Mead is a consultant neurologist and Clinical Lead of the UK National Prion Clinic based at the National Hospital for Neurology and Neurosurgery, UCLH. Also working at the UK Medical Research Council’s Prion Unit where he is Deputy Director, his research interests include treatments and preparations for clinical trials in CJD and other human prion diseases, the discovery of genetic and epigenetic factors that cause or modify prion disease. He was made a Professor at UCL in 2014, NIHR Senior Investigator in 2018.

Research Summary

Prions, composed of abnormally folded multimeric assemblies of host-encoded prion protein, cause fatal neurodegenerative conditions. They are seen as a model neurodegenerative condition, a group of disorders that represent a great challenge to healthcare systems in aging societies. Molecular genetics remains fundamental to understanding the aetiology of human prion disease.

Here are some examples of our groups work:

Human genetics has established the central importance of prion protein gene mutations and polymorphisms in human disease susceptibility, phenotypic modification and recent human evolution. We lead a global collaboration of DNA sample collection in prion disease and by genome wide association studies. We recently proposed variants in STX6 and GAL3ST1 are new genetic risk factors (Lancet Neurology 2020) and are now asking how these work. In other neurodegenerative diseases we collaborate and contribute samples to the leading efforts world-wide, some of these studies are landmarks in the field and were headline news stories around the world (Nat Genetics, Lancet Neurology). 

We also work on human evolution as the prion disease kuru, transmitted by cannibalism can occur in epidemics that cause intense selection pressure. We have described one of only a handful of examples of human evolutionary selection acting at a specific gene variant G127V in PRNP (NEJM 2009). Modelled in mouse, this change results in complete protection against prion disease (Nature 2015). New work aims to discover evidence of other loci that have evolved to protect against kuru.

We work on diagnosis and prediction in inherited prion disease, to support families and preventive medicine. In 2013 we reported a novel inherited prion disease called PrP systemic amyloidosis associated with diarrhoea and deposits of prion protein in all organs (NEJM 2013). The mutation that causes this disease removes the membrane anchor and truncates prion protein, emphasising the importance of this structure in the disease phenotype.

We helped develop a next generation sequencing panel for dementia (Neurobiol Aging 2014, Molecular Psychiatry 2018, Nature Reviews Neurology 2020), we have applied this in over 3200 samples and looked at the clinical and in silico predictors of carrying deleterious mutations in any of 17 dementia genes.

Following the recruitment of Dr Emmanuelle Vire, an accomplished scientist with experience in cancer biology, we work on epigenetics, meaning the study of dynamic chemical and structural changes in chromatin associated with persistently altered gene expression. We are assaying these changes genome wide in human and animal prion diseases, blood, brain and lymphoreticular tissue, to develop diagnostic tools and uncover molecular mechanisms. We have found evidence of altered DNA methylation (Acta Neuropathologica 2020) and miRNA profiles in blood (Nature Communications 2020).

We integrate our GWAS, exome, epigenetic and animal work to identify the networks and pathways involved in human prion disease together with the help of Dr Holger Hummerich, senior bioinformatician.

Teaching Summary

Simon supervises PhD and Masters students and lectures on several courses. In prion disease he has developed educational web resources (www.nationalprionclinic.org). At UCL he mentors neurologists and neurosurgeons on NIHR integrated academic training pathways. He has co-written several textbooks and review articles about prion diseases. 

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