Development and Use of Small-Molecule Activators of Neuroproteasomes to Treat ALS

Amyotrophic lateral sclerosis (ALS), which is known to many as Lou Gehrig's disease, is a devastating illness that attacks nerve cells. These cells control muscles throughout the body, and when the nerve cells stop working and die, the muscles become weak and paralyzed. There is currently no known cause of ALS, and no known cure.

The work described in this proposal reveals a new pathway forward in research to find the causes of and a cure for ALS. A central characteristic of many neurodegenerative diseases, including ALS, is the accumulation of certain types of toxic aggregates within our nerve cells. Our lab studies the newly discovered 'Neuronal Membrane Proteasome,' or NMP, which is a machine that acts like a garbage disposal in certain types of nerve cells, chopping up and throwing out the trash. We hypothesize that this newly discovered machine is malfunctioning in ALS patients; when the NMP isn't working, the trash piles up and forms aggregates. This proposal aims to find tools that can increase the activity of the NMP, and help it take out more of the trash. In collaborative cross-country work, we will first build the chemical tools to help NMPs do their job even better, based on preliminary work we have already carried out. We will then test the ability of these chemical tools to boost the function of NMPs in cells and in animals that have ALS symptoms. This will be the first test of whether NMPs can be targeted for therapeutic benefit -- first in ALS and in the future, for other neurodegenerative diseases. This will help us not only understand how NMPs work from a fundamental perspective but will provide the critical test of whether we can manipulate and control this system to help ALS patients.