Research Projects

Spinocerebellar ataxia-3 (SCA3) is a neurodegenerative disease characterized by ataxia and motor dysfunction, affecting the cerebellum, brainstem, and basal ganglia. The disease is caused by the tandem repeat expansion of CAG within the coding region of the Ataxin-3 protein, causing abnormal expansion of poly Glutamine. The longer forms are more pathogenic and genetic anticipation increases disease severity from generation to generation. The disorder is caused by the dominant gain of function due to the expansion of poly(Q) repeats within the ataxin-3 protein, which forms protein aggregates in the cytoplasm and axon projections and inclusion bodies (IB) in the nucleus. These aggregates bind to various cellular proteins, altering protein quality control mechanisms and sequestering transcription factors. No disease-modifying drug is available to prevent the progression of SCA3, and approved drugs only treat symptoms. Insulin resistance is most common among neurodegenerative disorders, including SCA3 and Alzheimer's disease. The study aims to dissect the role of the PI3K/Akt signaling pathway in the disease state and the possible therapeutic approach. Preliminary studies showed that overexpression of PI3K and Akt suppresses neurodegeneration in the SCA3 model, while knockdown of PTEN improved the eye phenotype and suppressed degeneration of mushroom body neurons. The study will genetically dissect the combinatorial approach by upregulating PI3K/Akt and Yki activity, and investigate the combinatorial approach in SCA3 fly models.