Project 462555

In Lou Gehrig's disease, also known as Amyotrophic Lateral Sclerosis (ALS), patients quickly lose their ability to control their muscles and their ability to swallow and breathe. Most patients only survive 2-5 years after diagnosis. There are only limited treatments available for ALS patients and these only modestly prolong survival. This means there is an important need for new treatments for ALS. ALS is a complex disease, with alterations in over 50 genes causing or increasing the risk of ALS, while over 80% of cases have unknown causes. Despite this wide spectrum of genetic and unknown causes nearly all patients with ALS accumulate clumps of a protein called TDP-43 in their cells. Causing TDP-43 to accumulate in mouse models used for research causes mice to develop cell death and symptoms that closely resemble ALS. This suggests that TDP-43 accumulation and clumping is an essential cause of ALS. Our goal is to understand the mechanisms that control the accumulation of TDP-43 in ALS and use this information to design new drugs to treat ALS. To do this we will study all 50 genes linked to ALS, to identify common pathways affecting TDP-43 accumulation. Our research suggests that one powerful way to control the accumulation of TDP-43 is by a garbage disposal process in cells called autophagy. We previously found that mutations in some genes which cause ALS can control the degradation of clumps of protein containing TDP-43 by autophagy. Our evidence suggests that the elimination of TDP-43 by autophagy is blocked in ALS patients. To overcome this, we designed a new type of drug that re-activates autophagy to target and eliminate TDP-43. Here, we will test how well these drugs work in mouse models of ALS with the aim of one day treating patients with this new type of drug. In sum, our aim with this funding is to understand the fundamental cellular processes that cause ALS and then apply this knowledge to develop new medicines for ALS patients.