Neurological Disorders: Modeling Neurological Disease in Drosophila

Drosophila provides a power genetic system to model neurological disease and identify genetic and pharmacological interactions that reduce or eliminate pathology, with the expectation some of the pathogenic mechanisms that are uncovered may be conserved with those found in human patients. Many neurodegenerative diseases associated with protein misfolding have been modeled in Drosophila. These models replicate key neuropathological features characteristic of the diseases, such as late onset, progressive neurodegeneration, and formation of inclusions containing the mutant protein. Huntington’s Disease (HD) is an adult-onset dominant heritable disorder characterized by progressive psychiatric disruption, cognitive deficits, and loss of motor coordination. It is caused by expansion of a polyglutamine (polyQ) tract within the N-terminal domain of the Huntingtin (Htt) protein. The mutation confers a toxic gain-of-function phenotype, resulting in neurodegeneration. There is currently no cure, and the disease is fatal approximately 15 to 20 years after the age of onset. How polyQ expansion within Htt causes HD is poorly understood. We have generated Drosophila HD transgenic models expressing fluorescently tagged wildtype and pathogenic Htt proteins that allow for in vivo imaging of Htt localization, axonal transport and aggregate formation in live animals. We have identified several pathologies associated with Htt polyQ expression in fly neurons, and have attempted to identify small molecules and genetic interactors that can revert HD pathology in our system. We are also studying mutants of the Drosophila Htt homolog to define the normal function of Htt within neurons.