Background Huntington's disease is a neurodegenerative disorder resulting from expansion of a polyglutamine tract in the huntingtin protein (Htt). Polyglutamine expansion in Htt leads to intracellular aggregates within neurons although it is unclear if aggregates or more soluble forms of mutant Htt represent the pathogenic species.
Aims/methods To search for modifiers of Huntington toxicity and genetically test the link between aggregation and neurodegeneration, we generated Drosophila melanogaster transgenic strains expressing fluorescently tagged human Htt encoding pathogenic (Q138) or non-pathogenic (Q15) proteins, allowing in vivo imaging of Htt expression and aggregation in live Drosophila. Neuronal expression of pathogenic Htt leads to pharate adult lethality, accompanied by the formation of large aggregates within the cytoplasm of neuronal cell bodies and neurites. We used this model to conduct haplo-insufficiency suppressor screens for HttQ138 aggregation or HttQ138 induced lethality using deficiencies covering ∼80% of the Drosophila genome.
Results We identified two classes of interacting deficiencies in our screen: those that rescue viability and decrease Htt levels and aggregation, and those that rescue viability independent of affects on HttQ138 aggregation. Haplo-insufficiency for several homoeotic genes contained within one of the larger deficiencies suppressed HttQ138 toxicity without reducing Htt expression or aggregation, indicating an unexpected link between homeodomain transcription factor activity and HttQ138 toxicity.
Conclusion The identification of dosage sensitive suppressors of mutant Htt toxicity that reduce lethality without disrupting aggregation suggests pathways downstream of aggregate formation can be targeted for neuroprotection in Huntington's disease.
- homoeotic transcription factor
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.