GSBS Dissertations and Theses

Approval Date

8-14-2016

Document Type

Master's Thesis

Academic Program

Interdisciplinary Graduate Program

Department

Molecular, Cell and Cancer Biology Department

First Thesis Advisor

Andreas Bergmann

Keywords

Frontotemporal Dementia, RNA-Binding Proteins, Endosomal Sorting Complexes Required for Transport

Subjects

Theses, UMMS; Frontotemporal Dementia; RNA-Binding Proteins; Endosomal Sorting Complexes Required for Transport

Abstract

Frontotemporal dementia (FTD) is the second most common early-onset dementia. A rare mutation in CHMP2B gene was found to be associated with FTD linked to chromosome 3. Previous studies have shown that mutant CHMP2B could lead to impaired autophagy pathway and altered RNA metabolism. However, it is still unknown what genes mediate the crosstalk between different pathways affected by mutant CHMP2B. Genetic screens designed to identify genes interacting with mutant CHMP2B represents a key approach in solving the puzzle. Expression of mutant CHMP2B (CHMP2Bintron5) in Drosophila eyes leads to a neurodegenerative phenotype including melanin deposition and disrupted internal structure of ommatidia. The phenotype is easily quantified by estimating the percentage of black dots on the surface of the eyes. Using this established Drosophila model, I searched for genes encoding RNA binding proteins that genetically modify CHMP2Bintron5 toxicity. I found that partial loss of Pumilio, a translation repressor, mitigates CHMP2Bintron5 induced toxicity in the fly eyes. Western blot analysis showed that down regulation of Pumilio does not significantly decrease CHMP2Bintron5 protein level, indicating indirect regulation involved in suppression of the phenotype. The molecular targets regulated by Pumilio and the mechanism underlying CHMP2Bintron5 toxicity suppression by Pumilio down-regulation requires further investigation.

DOI

10.13028/M27C7R

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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