Normal cells have a “self-cleaning” process called autophagy that breaks down and clears out cellular waste, so the cell can function properly. In the majority of ALS cases, a protein known as TDP-43 becomes misfolded and accumulates in motor neurons, causing toxicity. The accumulation of misfolded TDP-43 also occurs in people living with ALS who have a mutation in the C9orf72 gene, the most common genetic cause of ALS. The C9orf72 protein is known to play a role in autophagy and that role is diminished when the gene is mutated.
Recent animal experiments suggest that boosting autophagy with an experimental drug treatment can clear excess TDP-43 accumulation. Using human cells grown in culture and genetically-modified mice with depleted C9orf72, Lilian Lin will investigate whether the C9orf72 gene mutation and the associated loss of normal autophagy function increase TDP-43 protein misfolding and accumulation. If her hypothesis is correct, it will show an important connection between the two most prominently studied proteins in ALS and suggest that targeting this loss of autophagy might be a key avenue for the development of new ALS therapies.