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Fly (Austin). 2013 Oct-Dec;7(4):229-36. doi: 10.4161/fly.26279. Epub 2013 Sep 10.

Modeling Huntington disease in Drosophila: Insights into axonal transport defects and modifiers of toxicity.

Author information

1
The Picower Institute for Learning and Memory; Department of Brain and Cognitive Sciences; Department of Biology; Massachusetts Institute of Technology; Cambridge, MA USA.

Abstract

Huntington disease (HD) is an inherited neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the huntingtin (Htt) gene. Despite years of research, there is no treatment that extends life for patients with the disorder. Similarly, little is known about which cellular pathways that are altered by pathogenic Huntingtin (Htt) protein expression are correlated with neuronal loss. As part of a longstanding effort to gain insights into HD pathology, we have been studying the protein in the context of the fruitfly Drosophila melanogaster. We generated transgenic HD models in Drosophila by engineering flies that carry a 12-exon fragment of the human Htt gene with or without the toxic trinucleotide repeat expansion. We also created variants with a monomeric red fluorescent protein (mRFP) tag fused to Htt that allows in vivo imaging of Htt protein localization and aggregation. While wild-type Htt remains diffuse throughout the cytoplasm of cells, pathogenic Htt forms insoluble aggregates that accumulate in neuronal soma and axons. Aggregates can physically block transport of numerous organelles along the axon. We have also observed that aggregates are formed quickly, within just a few hours of mutant Htt expression. To explore mechanisms of neurodegeneration in our HD model, we performed in vivo and in vitro screens to search for modifiers of viability and pathogenic Htt aggregation. Our results identified several novel candidates for HD therapeutics that can now be tested in mammalian models of HD. Furthermore, these experiments have highlighted the complex relationship between aggregates and toxicity that exists in HD.

KEYWORDS:

Drosophila; Huntington disease; aggregates; axonal transport; polyglutamine

PMID:
24022020
PMCID:
PMC3896494
DOI:
10.4161/fly.26279
[Indexed for MEDLINE]
Free PMC Article

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