Date of Completion

Spring 5-12-2013

Thesis Advisor(s)

Ping Zhang

Honors Major

Molecular and Cell Biology

Disciplines

Cell Biology | Molecular Biology

Abstract

Human CAG repeat diseases manifest themselves through the common pathology of neurodeneration. This pathological link is attributed to the property shared by all nine of these diseases: an expanded polyglutamine (polyQ) tract. The most evident result of polyQ expansion is protein aggregation, and it is believed that this phenomenon is partly responsible for conferring cytotoxic properties on the mutated protein. Apart from sequestering the mutated protein, cellular aggregates are able to incorporate native proteins via polyQ-mediated aggregation, thus disrupting important cellular pathways. Using Drosophila melanogaster as a disease model, researchers have been able to compile collections of these so-called disease modifiers for most of the CAG repeat diseases. Moreover, a recently characterized Drosophila gene, Dikar, appears to synergistically react with polyQ-expanded proteins in an especially strong fashion, causing a synthetic lethal phenotype. One potential mechanism by which Dikar causes synthetic lethality involves the genetic construct used to achieve ectopic gene expression: the Gal4-UAS system in conjunction with the Drosophila eye-specific transcription factor Glass and its enhancer sequence GMR. A suspected chromatin remodeling complex, Dikar may create a feedback loop involving GMR that would result in increased polyQ expression and thus cell death. To test whether this phenomenon was responsible for synthetic lethality, a (GFP) reporter gene assay was carried out using two versions of GMR: longGMR and shortGMR. The findings of this study demonstrated that Dikar did not affect GMR-driven expression levels of the GFP reporter. Therefore, it was concluded that synthetic lethality is not the result of a self-perpetuating circuit but rather involves either direct or indirect interactions between Dikar and the polyQ protein.

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