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  1. Evaluation Summary:

    This is important work trying to decipher some of the potential benefits and pathways from exercise. SCA2 was most impacted by exercise, and this correlated with Sestrin increases that proportionally led to decreases in the disease causing SCA2 protein (but not SCA3 so much). Sestrin alone was able to affect the disease severity in SCA2 flies, via the interaction with mTOR and the autophagy pathway.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)

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  2. Reviewer #1 (Public Review):

    The ability of exercise to mitigate the disease-associated phenotypes for the inherited ataxias is an area under investigation for several years. Previous studies explore the ability of endurance exercise to promote neuronal plasticity and memory as well as diminish neurodegeneration. Here the investigators examine the therapeutic ability of endurance exercise to disease in drosophila models of the spinocerebellar ataxias types (SCAs) 2, 3, and 6. Chronic exercise was found to strongly impact motor performance of SCA2 flies, moderately impact disease in SCA6 flies and have no effect on SCA3 fly disease. Interestingly, the exercise-inducible protein, Sestrin (Sesn) reduced mutant Atxn2 and suppressed disease in unexercised SCA2 flies. This study adds important new insight into the link between exercise and its potential to mitigate SCA disease.

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  3. Reviewer #2 (Public Review):

    This is important work trying to decipher some of the potential benefits and pathways from exercise. Although it is interesting that the strongest effects were seen with SCA2, but less SCA3 and not SCA6 at all, the authors did an adequate job in not overly interpreting and extrapolating to vertebrate models or humans. SCA2 was most impacted by exercise, and this correlated with Sestrin increases that proportionally led to decreases in the disease causing SCA2 protein (but not SCA3 so much). Thus, the remainder of the mechanistic studies focus on SCA2. Importantly, Sestrin alone was able to affect the disease severity in SCA2 flies, and the authors used specific point mutants to address specificity of this activity via the interaction with mTOR and the autophagy pathway, though more convincing evidence of the role of autophagy is necessary to make this claim.

    One concern for almost every figure legend is a lack of information on number of flies or samples per group and the exact statistical comparisons and post-hoc tests used. It is far more useful to have this information directly in the figure legend, especially for readers who go straight to the figures and do not focus on the text as much. For example, Fig 2 states N>100, n>8 vials of 20 flies, but do the data points represent the mean of each vial's average, or N>100 as an entire group? What statistical test is used? The same is true for Fig 3-6, and additionally these figures lack information on how many vials were in each group (i.e. are there any batch effects from vials that could skew the results?).

    The data for Figure 7 is the key supporting evidence of the claim that this is operating via autophagy. However, given the variability in the data and the very small sample sizes N=3-4/group, this is not currently supported. For example, the effects of the dSEN WT expression on ATXN2 protein levels is only significant because the grouping is tighter but there is a decrease in the other dSesn mutants. Same is true for AtgIa/IIa ratios where there is some effect of the dSesn mutant expression but just more variability. Either more samples are needed, or these data and claims should be removed from the manuscript.

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  4. Reviewer #3 (Public Review):

    The manuscript entitled "Endurance exercise ameliorates phenotypes 1 in Drosophila models of 2 Spinocerebellar Ataxias" by Sujowski et al., presents an interesting role of endurance exercise in rescuing the Spinocerebellar Ataxias Type 2 (SCA2). The manuscript highlights the role of endurance exercise, with widespread benefits, using the fly model of SCA2, 3 and 6. In Drosophila model of SCA2,3 and 6, they found marked protection of speed and endurance in exercised SCA2 flies and modest protection in exercised SCA6 and no benefit is observed in SCA3 flies. In the SCA2 model only, the causative protein SCA2 levels were reduced through induction of exercise-inducible protein Sestrin (Sesn). Furthermore, they found that high levels of Sesn can decrease levels of disease protein SCA2 even without exercise, and through increased autophagic flux. Sesn protein includes domains that reduce oxidative damage and modulate mTOR activity. This study demonstrates differential responses of polyQ SCAs to exercise, highlighting the potential for more extensive application of exercise-based therapies in the prevention of polyQ neurodegeneration. This study defines the mechanisms by which endurance exercise suppresses polyQ SCAs will open the door for more effective treatment for these diseases.

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