Chris Shaw Group
My team have sought to understand what causes amyotrophic lateral sclerosis (ALS, also known as motor neuron disease, MND) and fronto-temporal dementia (FTD) with the aim of finding more effective therapies. ALS causes muscular paralysis due the degeneration of motor neurons in the spinal cord. FTD causes distressing changes in personality, behavioural and language. Both are relentless in their progression and no treatments dramatically alter the disease course.
Over the past 20 years our patients with ALS and FTD have generously donated DNA samples, lymphoblast cell lines and post mortem tissues to support our research. To date we have identified six novel disease causing genes and several major disease pathways that have advanced the prospect of drug discovery. Following the discovery by Neumann et al. (2006) that TDP-43 was the dominant protein aggregating in FTD and ALS, my lab were the first to identify mutations in familial and sporadic ALS and demonstrate their neurotoxicity (Sreedharan 2008). This proved that TDP-43 accumulation in the cytoplasm was the major toxic insult in these two conditions. We have subsequently identified the proteins that regulate TDP-43 nucleo-cytoplasmic shuttling (Nishimura 2010), identified the major RNA binding targets and characterised splicing changes in following TDP-43 knockdown, and in patients brains with FTD and healthy aging (Tollervey 2011a and b). With key colleagues we have generated stem cells from patient skin fibroblasts and shown that neurons and glia derived from patients carrying TDP-43 mutations recapitulate key features of ALS and FTD pathology (Bilican 2012, Serio 2013, Barmada 2014, Devlin 2015). We have also generated TDP-43 mutant transgenic mice that develop progressive paralysis and show changes in the brain and spinal cord typical of FTD and ALS (Mitchell 2015). Recently we have shown that activation of Heat Shock Factor 1 leads to a dramatic clearance of TDP-43 from neurons.
Using genome-wide linkage we identified a novel locus for familial ALS on chromosome 16q (Ruddy 2003) and subsequently identified mutations in another RNA binding protein, FUS in familial ALS cases and were the first to demonstrate that FUS mutations disrupt the nuclear localising signal leading to cytoplasmic aggregates (Vance 2009). We subsequently generated a transgenic mouse model with FUS overexpression leading to an ALS phenotype (Mitchell 2013). We were also the first to demonstrate linkage to Chromosome 9p in a Dutch ALS and FTD kindred (Vance 2006). An expanded hexanucleotide repeat was subsequently shown by two groups DeJesus-Hernandez (2013) and Renton (2013) to be the most common mutation for ALS and FTDTDP. Subsequently we demonstrated the hallmark inclusion pathology in C9orf72 cases (Al-Sarraj 2011), that specific RNA binding proteins are sequestered in RNA foci (Lee 2013). We have shown that specific dipeptide repeat proteins expressed in C9orf72 cases are toxic (Lee 2017) but are extremely rare in ALS spinal cord (Gomez-Deza 2015). Our exome sequencing effort in familial ALS is ongoing with a recent discovery of mutations in TUBA4A (Smith 2014), ANXA11 (Smith 2017) and several other unpublished candidates undergoing functional studies.