Differential response of neurons to autophagy modulation in Huntington’s disease

Jul 3, 2025Autophagy reports

Different ways nerve cells respond to changes in their recycling process in Huntington's disease

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

In male fruit flies, modulation of the pathway improved the toxic effects of mutant HTT protein in circadian neurons and those regulating carbohydrate and lipid metabolism.

Not all neurons expressing mutant HTT protein show a positive response to autophagy modulation.
Motor neurons and those involved in temperature regulation did not demonstrate improvement.
Specific changes in mutant HTT and autophagy markers were observed in the responsive neurons.
These findings may explain the limited success of autophagy modulators in clinical trials for .

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(HD) is caused by the expansion of poly-glutamine repeats in the Huntingtin () gene and is associated with a wide variety of motor and physiological (sleep, metabolism, etc.) perturbations. Studies from diverse model organisms have proposed that modulation of (a key protein homeostatic pathway) can mitigate the toxic effects of mutant HTT protein. However, consistent changes are not observed across studies, and the improvements in phenotypes can be associated with changes in specific circuits/neurons affected by the mutant HTT protein. They suggest that not all neurons respond effectively to autophagy modulation. Hence, it remains to be understood whether diverse circuits/neurons affected by mutant HTT protein respond effectively to this intervention. Using a genetic approach, we expressed mutant HTT protein independently in diverse sets of neurons in maleand asked whether genetic modulation of autophagy pathway throughoverexpression can mitigate the toxic effect of mutant HTT protein. We found that in male flies, not all neurons/circuits expressing mutant HTT protein respond effectively to ATG8a protein. Circadian neurons and neurons regulating carbohydrate and lipid metabolism () showed improvement, while motor and neurons responding to temperature changes showed no improvement. Using cellular markers we also showed that these phenotypes can be attributed to specific changes in mutant HTT and Ref(2)P proteins (autophagy marker). Our study suggests that not all circuits respond effectively to autophagy modulation and suggests a potential cause for low success of autophagy modulators in clinical trials.. Htt Drosophila melanogaster Atg8a Dilp2 +ve

Key numbers

138 h

Increased Lifespan

Mean lifespan of flies expressing mutant HTT-Q128 protein.

significant reduction

Wet Weight Reduction

Comparison of wet weights across genotypes.

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Differential response of neurons to autophagy modulation in Huntington’s disease

Abstract

Key numbers

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