157 Oral - Models of Human Disease I - Diseases with a Neurological Focus
Saturday April 09, 9:15 AM - 9:30 AM

Authors:
Alyson Sujkowski ¹; Kristin Richardson ¹; Matthew Prifti ²; RJ Wessells ¹; Sokol Todi ^{2, 3}

Affiliations:
1) Wayne State University School of Medicine Department of Physiology, Detroit, MI; 2) Wayne State University School of Medicine Department of Pharmacology, Detroit, MI; 3) Wayne State University School of Medicine Department of Neurology, Detroit, MI

Keywords:
d. trinucleotide repeat expansion; m. TOR signaling

Endurance exercise is a potent intervention with widespread benefits proven to reduce disease incidence and impact. While endurance exercise supports neural plasticity, enhanced memory, and reduced neurodegeneration, less is known about the effect of chronic exercise on the progression of movement disorders such as ataxias. Here, we focused on three different types of ataxias, Spinocerebellar Ataxias Type (SCAs) 2, 3 and 6, belonging to the polyglutamine (polyQ) family of neurodegenerative disorders. In Drosophila models of these SCAs, flies progressively lose motor function and accumulate levels of toxic SCAproteins. Excitingly, we observe dramatic protection of speed and endurance in exercised SCA2 flies and modest protection in exercised SCA6 models, while no benefit is observed in SCA3. Importantly, causative protein levels are reduced in SCA2 flies after chronic exercise, but not in SCA3 models, linking protein levels to exercise-based benefits. Currently, we are focusing on the activation of exercise-mimicking genes in SCA-model flies to define the mechanisms by which exercise preserves function in polyQ ataxias. The exercise-inducible protein dSestrin suppresses longitudinal mobility defects and improves early mortality in SCA2 flies, even without exercise. Furthermore, overexpression of dSestrin mimics exercise-induced reductions in disease protein in SCA2 flies by increasing autophagy. These improvements critically depend on previously-established functions of dSestrin that reduce oxidative damage and modulate mTOR activity. Our study suggests differential responses of ataxias to exercise, highlighting the potential for more extensive application of exercise-based therapies in the prevention of polyQ neurodegeneration.