Endurance exercise is a potent intervention with widespread benefits proven to reduce disease incidence and impact across species. 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. In this study, we observe marked protection of speed and endurance in exercised SCA2 flies and modest protection in exercised SCA6 models, with no benefit to SCA3 flies. Causative protein levels are reduced in SCA2 flies after chronic exercise, but not in SCA3 models, linking protein levels to exercise-based benefits. Further mechanistic investigation indicates that the exercise-inducible protein, Sestrin (Sesn), suppresses mobility decline and improves early death in SCA2 flies, even without exercise, coincident with disease protein level reduction and increased autophagic flux. These improvements depend on previously established functions of Sesn that reduce oxidative damage and modulate mTOR activity. Our study suggests differential responses of polyQ SCAs to exercise, highlighting the potential for more extensive application of exercise-based therapies in the prevention of polyQ neurodegeneration. Defining the mechanisms by which endurance exercise suppresses polyQ SCAs will open the door for more effective treatment for these diseases.
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures and supplementary information.
- Alyson Sujkowski
- Robert J Wessells
- Robert J Wessells
- Sokol V Todi
- Sokol V Todi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Harry T Orr, University of Minnesota, United States
- Received: November 8, 2021
- Preprint posted: December 7, 2021 (view preprint)
- Accepted: February 15, 2022
- Accepted Manuscript published: February 16, 2022 (version 1)
- Accepted Manuscript updated: February 17, 2022 (version 2)
- Version of Record published: February 24, 2022 (version 3)
- Version of Record updated: March 8, 2022 (version 4)
- Version of Record updated: May 18, 2022 (version 5)
© 2022, Sujkowski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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