Amyotrophic lateral sclerosis (also known as motor neuron disease) is a devastating neurodegenerative disease in which motor neurons specifically degenerate leading to paralysis and death. The majority of cases are sporadic (90%) where there is no discernable cause, the remaining cases are termed familial due to mutations being identified and linked to the disease in several different genes. One such gene encodes the protein superoxide dismutase-1, an enzyme that scavenges superoxide in the intracellular millieu and converts it to less toxic substances. Surprisingly, mutations in SOD1 don't cause ALS through a loss of function, but rather through a toxic gain of function. The toxic gain of function is considered to be associated with the impaired folding of the protein leading to generation of misfolded conformations and protein aggregates.
I seek to understand the process of SOD1 (and other proteins) misfolding, aggregation, and pathological spread, so that effective therapeutics can be generated to halt the progression of ALS/MND.
McAlary L, Aquilina J.A, Yerbury J.J (2016), Susceptibility of mutant SOD1 to form a destabilized monomer predicts cellular aggregation and toxicity but not in vitro aggregation propensity, Frontiers in Neuroscience 10, http://dx.doi.org/10.3389/fnins.2016.00499
Whiten D.R, San Gil R, McAlary L, Yerbury J.J, Ecroyd H, Wilson M.R (2016) Rapid flow cytometric measurement of protein inclusions and nuclear trafficking, Scientific Reports 6, doi:10.1038/srep31138
McAlary L, Yerbury J.J, Aquilina J.A (2013), Glutathionylation potentiates benign superoxide dismutase 1 variants to the toxic forms associated with amyotrophic lateral sclerosis, Scientific Reports 3, doi:10.1038/srep03275