Restoration of Sleep and Circadian Behavior by Autophagy Modulation in Huntington's Disease

Circadian and sleep defects are well documented in Huntington's disease (HD). Modulation of the autophagy pathway has been shown to mitigate toxic effects of mutant Huntingtin (HTT) protein. However, it is not clear whether autophagy induc-tion can also rescue circadian and sleep defects. Using a genetic approach, we expressed human mutant HTT protein in a subset of Drosophila circadian neurons and sleep center neurons. In this context, we examined the contribution of autophagy in mitigating toxicity caused by mutant HTT protein. We found that targeted overexpression of an autophagy gene, Atg8a in male flies, induces autophagy pathway and partially rescues several HTT-induced behavioral defects, including sleep fragmen-tation, a key hallmark of many neurodegenerative disorders. Using cellular markers and genetic approaches, we demonstrate that indeed the autophagy pathway is involved in behavioral rescue. Surprisingly, despite behavioral rescue and evidence for the involvement of the autophagy pathway, the large visible aggregates of mutant HTT protein were not eliminated. We show that the rescue in behavior is associated with increased mutant protein aggregation and possibly enhanced output from the targeted neurons, resulting in the strengthening of downstream circuits. Overall, our study suggests that, in the presence of mutant HTT protein, Atg8a induces autophagy and improves the functioning of circadian and sleep circuits.

Automated summary

This study investigates whether autophagy induction can rescue circadian and sleep defects caused by mutant HTT protein. The researchers expressed human mutant HTT protein in specific Drosophila neurons and found that targeted overexpression of the autophagy gene Atg8a partially rescued several HTT-induced behavioral defects. Surprisingly, while behavior was improved, the visible aggregates of mutant HTT protein were not eliminated, suggesting that autophagy could enhance neuronal output and strengthen downstream circuits.