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Endurance exercise ameliorates phenotypes in Drosophila models of spinocerebellar ataxias

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 progressio...

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Autores principales: Sujkowski, Alyson, Richardson, Kristin, Prifti, Matthew V, Wessells, Robert J, Todi, Sokol V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8871352/
https://www.ncbi.nlm.nih.gov/pubmed/35170431
http://dx.doi.org/10.7554/eLife.75389
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author Sujkowski, Alyson
Richardson, Kristin
Prifti, Matthew V
Wessells, Robert J
Todi, Sokol V
author_facet Sujkowski, Alyson
Richardson, Kristin
Prifti, Matthew V
Wessells, Robert J
Todi, Sokol V
author_sort Sujkowski, Alyson
collection PubMed
description 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 partially 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.
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spelling pubmed-88713522022-02-25 Endurance exercise ameliorates phenotypes in Drosophila models of spinocerebellar ataxias Sujkowski, Alyson Richardson, Kristin Prifti, Matthew V Wessells, Robert J Todi, Sokol V eLife Neuroscience 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 partially 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. eLife Sciences Publications, Ltd 2022-02-16 /pmc/articles/PMC8871352/ /pubmed/35170431 http://dx.doi.org/10.7554/eLife.75389 Text en © 2022, Sujkowski et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Neuroscience
Sujkowski, Alyson
Richardson, Kristin
Prifti, Matthew V
Wessells, Robert J
Todi, Sokol V
Endurance exercise ameliorates phenotypes in Drosophila models of spinocerebellar ataxias
title Endurance exercise ameliorates phenotypes in Drosophila models of spinocerebellar ataxias
title_full Endurance exercise ameliorates phenotypes in Drosophila models of spinocerebellar ataxias
title_fullStr Endurance exercise ameliorates phenotypes in Drosophila models of spinocerebellar ataxias
title_full_unstemmed Endurance exercise ameliorates phenotypes in Drosophila models of spinocerebellar ataxias
title_short Endurance exercise ameliorates phenotypes in Drosophila models of spinocerebellar ataxias
title_sort endurance exercise ameliorates phenotypes in drosophila models of spinocerebellar ataxias
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8871352/
https://www.ncbi.nlm.nih.gov/pubmed/35170431
http://dx.doi.org/10.7554/eLife.75389
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