Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are incurable conditions characterized by the progressive loss of muscle strength and early-onset dementia, respectively. One thing these conditions have in common is the presence of aggregates of the protein TDP-43 in dying neurons. Since mutations in TDP-43 can cause ALS, the TDP-43 aggregates are believed to be the driving force of the progressive loss of neurons. Our lab has discovered a unique and novel mutation in the TDP-43 protein that causes a progressive muscle disease distinct from ALS or FTD in an extended Belgian pedigree, thereby establishing for the first time a primary pathogenic role for
TDP-43 in muscle degeneration. Interestingly, recent research revealed that accumulations of TDP-43 can also be found in the cells of muscle tissue of ALS patients, as well as other non-ALS-related muscular degenerative conditions. Based on these findings and our genetic
discovery, we propose to study the mechanism by which TDP-43 accumulation in muscle contributes to the disease process in our myopathy family as well as ALS. It is our belief that our work will open new avenues for the identification of novel therapeutic targets.