Prof Christopher Shaw
Christopher Shaw is Professor of Neurology and Neurogenetics at King’s College London. His clinical training was conducted in New Zealand and in 1992 he ventured to Cambridge, UK on a Wellcome Trust Fellowship. In 1995 he moved to King’s College London and King’s College Hospital – where he trained in Neurogenetics, and his clinical and research interest became focused on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Under Christopher’s stewardship, the Department of Basic and Clinical Neuroscience grew from 10 to 40 Principal Investigators over a 10-year period. He led an initiative to build a new Neuroscience research facility by making the strategic case for colocation, led the design brief and raised the £50m required to build and equip the 10,000sqm Maurice Wohl Clinical Neuroscience Institute. It opened in June 2015, providing exceptional wet-laboratory and microscopy facilities. He subsequently led a successful £15m bid to host a United Kingdom Research Institute Centre within the Wohl.
Christopher and his research team have discovered more ALS and FTD genes than another other laboratory, and have created one of the world’s largest Biobanks of post mortem tissues, DNA samples, lymphoblast and induced pluripotent cell lines from patients with ALS and FTD. This has underpinned his research exploring the genetics, molecular and cellular pathobiology of ALS and FTD which has led to the publication of >230 peer reviewed papers, cited >17,500 times generating an H index of 67. They have developed stem cell and transgenic mouse models of disease that have revealed important insights into disease mechanisms and novel drug targets.
His team identified many novel SOD1 mutations and described the associated molecular pathology. They were the first to identify mutations in TDP-43 in familial and sporadic ALS and demonstrate toxicity in vivo. They subsequently identified the mechanisms regulating TDP-43 nucleocytoplasmic shuttling, identified the major RNA binding targets and the pathways regulating its proteolysis. They have generated mutant TDP-43 transgenic mice, patient induced pluripotent stem cells, IPS-derived neurons and glia from TDP-43 mutant patients that recapitulate key features of human ALS pathology.
Using genome-wide linkage they identified a novel locus for familial ALS on chromosome 16q. Subsequently they identified mutations (FUS) and were the first to demonstrate that FUS mutations disrupt the nuclear localizing signal leading to cytoplasmic aggregation. They generated the first transgenic mouse model demonstrating that FUS overexpression leads to an ALS phenotype with a dying back axonopathy.
They were the first to demonstrate linkage to Chromosome 9p in an ALS and frontotemporal dementia (FTD) kindred subsequently shown by others to be an expanded G4C2 hexanucleotide repeat and the most common mutation for ALS and FTD.
Subsequently they discovered the hallmark cerebellar pathology in C9-ALS and FTD and the RNA binding proteins that bind to RNA foci. Their exome/genome sequencing is on-going, with recent discoveries including mutations in TUBA4A, NEK1, Annexin A11 and ARPP21. Their major focus for the future is to develop gene therapies using antisense oligonucleotides and adeno-associated viral gene vectors.