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Updated: Jul 13, 2025
Monitoring Cell-to-cell Transmission of Prion-like Protein Aggregates in Drosophila Melanogaster
Published on: March 12, 2018
Rapamycin reduces neuronal mutant huntingtin aggregation and ameliorates locomotor performance in Drosophila
Jonathan R Roth1,2, Ruan Carlos Macedo de Moraes1, Brittney P Xu1
1Department of Pathology, Cellular and Molecular Division, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Insights
Neuronal mutant huntingtin causes brain aggregation and locomotor deficits in Huntington's disease (HD) models. Rapamycin treatment reduced this aggregation, suggesting brain-periphery crosstalk is key to HD.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder.
- HD stems from a CAG expansion in the HTT gene, causing polyglutamine (PQ) repeats in huntingtin protein.
- Previous studies linked peripheral Htt-PQ aggregation to cardiac dysfunction in Drosophila models.
Purpose of the Study:
- Investigate the impact of neuronal mutant huntingtin on peripheral function.
- Examine the role of brain-periphery crosstalk in HD pathogenesis.
- Assess the efficacy of rapamycin in reducing mutant huntingtin aggregation in the brain.
Main Methods:
- Overexpression of normal (Htt-PQ25) and mutant (Htt-PQ72) huntingtin exon 1 in Drosophila neurons.
- Assessed age-dependent Htt-PQ aggregation and synapsin loss in the brain.
- Evaluated locomotor performance using negative geotaxis assays.
- Administered rapamycin to observe its effect on Htt-PQ aggregation.
Main Results:
- Neuronal expression of mutant huntingtin led to age-dependent Htt-PQ aggregation in the brain.
- Mutant huntingtin expression caused loss of synapsin and decreased locomotor performance.
- Rapamycin treatment effectively reduced Htt-PQ aggregation within the brain.
Conclusions:
- Neuronal mutant huntingtin plays a significant role in dysfunction observed in HD models.
- Brain-periphery interactions are potentially crucial in the pathogenesis of Huntington's disease.
- Rapamycin demonstrates potential in reducing mutant huntingtin aggregation in the brain.
Abstract:
Huntington's disease (HD) is a neurodegenerative disease characterized by movement and cognitive dysfunction. HD is caused by a CAG expansion in exon 1 of the HTT gene that leads to a polyglutamine (PQ) repeat in the huntingtin protein, which aggregates in the brain and periphery. Previously, we used Drosophila models to determine that Htt-PQ aggregation in the heart causes shortened lifespan and cardiac dysfunction that is ameliorated by promoting chaperonin function or reducing oxidative stress. Here, we further study the role of neuronal mutant huntingtin and how it affects peripheral function. We overexpressed normal (Htt-PQ25) or expanded mutant (Htt-PQ72) exon 1 of huntingtin in Drosophila neurons and found that mutant huntingtin caused age-dependent Htt-PQ aggregation in the brain and could cause a loss of synapsin. To determine if this neuronal dysfunction led to peripheral dysfunction, we performed a negative geotaxis assay to measure locomotor performance and found that neuronal mutant huntingtin caused an age-dependent decrease in locomotor performance. Next, we found that rapamycin reduced Htt-PQ aggregation in the brain. These results demonstrate the role of neuronal Htt-PQ in dysfunction in models of HD, suggest that brain-periphery crosstalk could be important to the pathogenesis of HD, and show that rapamycin reduces mutant huntingtin aggregation in the brain.
