Dr. Cashman will receive additional support to work on the connections between two prominent ALS proteins, SOD1 and TDP-43. In ALS, TDP-43 is a protein that is abnormally shaped (called “misfolded”) and found in the wrong location in cells in 98% of cases. His hypothesis is that in sporadic ALS, this mislocalized, misfolded TDP-43 causes further misfolding of SOD1, and thus starts a domino effect of misfolded SOD1 and spreading of pathology throughout the body. Last year, he received a two year Bridge Grant to explore the following:
Though SOD1 and TDP-43 were the first two prominent genetic factors discovered in ALS, our understanding of their unique functions did not yield many studies examining a relationship between them in the ALS disease process. Dr. Cashman aims to first examine if abnormal structure of normal, non-mutant SOD1 (wild-type SOD1), which is termed “misfolding”, can cause neuronal death, as well as the mechanism by which this may occur. When SOD1 has a mutation, it misfolds and can cause familial (hereditary) ALS. Demonstration that misfolded wild-type forms can cause neurodegeneration would implicate SOD1 in sporadic ALS as well. Uniquely, he will then examine if mutations in TDP-43 can trigger wild-type SOD1 misfolding in cell cultures and possibly model ALS disease in a novel mouse model designed to study this connection.
To complement that work, Dr. Cashman will explore how a specific amino acid on TDP-43 called tryptophan might confer the ability to cause SOD1 misfolding. Proteins consist of long chains of substances called amino acids and Dr. Cashman had previously shown that a specific tryptophan amino acid is critical to SOD1 misfolding that he hypothesizes as starting a misfolding cascade that leads to ALS spread throughout the body. Recently he has determined that tryptophans on TDP-43 may also be key component to their ability to cause subsequent SOD1 misfolding. Using the 2016 Bridge funds, he will work to determine which tryptophan amino acids in the TDP-43 sequence are important for this function. If identified and his hypothesis is proven correct, this may represent a very plausible target for therapy, especially given modern technology of genetic modification (like CRISPR) that could alter these tryptophans to something innocuous.