Behavioral and Molecular Alterations in Drosophila with Modulated IK2/TBK1 Gene Expressions - Abstract Neurodegenerative diseases are one of the leading causes of mortality in the United States. Among them, amyotrophic lateral sclerosis (ALS) is prominent because it is rapidly progressing and there is no effective cure to date. ALS can be sporadic or familial, and mutations in many genes were found to contribute to the pathogenesis of both familial and sporadic ALS, although how the malfunction of these genes leads to ALS is still not fully understood. Recently, mutations in the TBK1 gene were identified in ALS patients. Although the TBK1 gene encodes a protein kinase that participates in autophagy and inflammation, how such mutations confer ALS pathogenesis is not well characterized due to the lack of animal models. Fruit flies (Drosophila melanogaster) are widely used to model human diseases, including neurodegenerative disorders. In the fruit fly, the TBK1 orthologue gene IK2 was reported to play roles in caspase activation, RNA localization, and neuron dendrite remodeling, and the lack of IK2 could lead to a lethal phenotype. In order to better understand the molecular mechanisms of mutant TBK1-associated ALS, the research proposed here will use Drosophila genetic analysis and cellular and molecular tools to assess the impact of the overexpression of human wild-type and ALS-mutant TBK1, along with the loss of the IK2 gene, in fruit flies, with an emphasis on nervous system function. We plan to address these questions in the following aspects: 1. The behavioral and molecular changes of fruit flies with the overexpression of wild-type and mutant TBK1 gene or the loss of IK2 gene; 2. The alteration of molecular pathways in IK2 deficient flies with the overexpression of wild-type and mutant TBK1 gene or the loss of IK2 gene; 3. The genetic and molecular interactions of the wild-type or mutant TBK1 gene or altered IK2 gene with other ALS-causing mutant genes in fruit flies. We believe these ideas are novel and of high importance for ALS and neurodegenerative disease research.
