We are focused on understanding the way by which neurons are lost in the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). ALS is also known as Lou Gehrig's Disease and Motor Neuron Disease.
We study fundamental cellular processes using a wide range of experimental approaches from cell biology, biochemistry, and neuroscience to determine the signalling mechanisms affected in ALS. We use mammalian tissue culture models, including primary neurons, validated rodent models of disease, and human patient samples to determine the biology that underlies ALS. It is our intent to apply our findings to the development of therapeutics and biomarkers.
Our primary research interests are to understand the role of certain RNA binding proteins, including TDP-43, hnRNP A1, and G3BP1. Some of these are directly relevant to ALS pathogenesis, others are an exploration of fundamental biology.
We also have long standing interest in understanding misfolded SOD1 and its contribution to familial SOD1-mediated disease.
TDP-43 AND RNA GRANULES
Li et al., JCB, 2013
One first-line protective mechanism by which a cell responds to an adverse environmental insult or stressor is the formation of stress granules (SGs). The primary impetus of the process favours cellular recovery, thus a failure of this system can have drastic consequences. There is increasing evidence that a failure of the SG response is critical to the pathobiology of ALS. We have discovered that TDP-43 regulates SG assembly in such a way as to disrupt SG interactions with other RNA granules. A deeper understanding of this mechanism will provide essential knowledge for the design of new strategies for the management and treatment of both sporadic and familial ALS.
New work also includes exploration of the role of TDP-43 in the alternative splicing of hnRNP A1, another ALS-related RNA binding protein.
We have previoulsy investigated the consequences of superoxide dismutase 1 (SOD1) misfolding. The ALS research community largely agrees that misfolded SOD1 lies at the root of toxicity in familial ALS. We have demonstrated that several SOD1 mutants adopt a misfolded conformation that preferentially and progressively associates with the surface of spinal cord mitochondria prior to disease onset.