Defense Date

2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Human Genetics

First Advisor

Mike Grotewiel

Abstract

Aging is an intrinsic process that is independent of obvious disease. In contrast to normal aging, age-related diseases are conditions that typically manifest at advanced ages, are associated with explicit pathology and cause disability and premature death. We used Drosophila as a model to investigate the molecular-genetic mechanisms associated with aging and age-related disease. Age-related locomotor impairment (ARLI) is a serious condition for the elderly and greatly impacts their quality of life. Toward identifying genes and mechanisms that influence ARLI, we performed a forward genetic screen using Drosophila mutants. This screen identified a loss of function mutant in PDK1, a component of the insulin signaling pathway. Additional loss of function mutants in the insulin signaling pathway genes PI3K Dp110, and AKT also delayed ARLI. These results suggest a role for insulin signaling in ARLI. Wolfram Syndrome (WFS) is a progressive neurodegenerative disease that is caused by mutations in the genes WFS1 and CISD2. The function of CISD2, the most recently identified gene has not been fully resolved. We used RNAi to knockdown wfs2, the fly ortholog of CISD2 to identify genes and pathways associated with wfs2 that will provide insight into the normal function of this gene. Through a targeted genetic screen in the Drosophila eye we identified that wfs2 interacts with two lysosomal storage disease genes PPT1 and CLN3. These results suggest that WFS and lysosomal storage diseases may be influenced by common molecular-genetic mechanisms. Furthermore, wfs2 may play a role in the neurodegenerative pathways associated with lysosomal storage disease. Oxidative stress is associated with aging and age-related disease. To identify genes that can protect against endogenous oxidative stress we performed a candidate suppressor screen. This screen revealed that expression of wild-type Ataxin-3 suppressed the short lifespan of Sod2 knockdown flies. The ubiquitin associated function of Ataxin-3 was determined to be important for this suppression. Interestingly, Ataxin-3 expression also extended the short lifespan due to knockdown of thioredoxin reductase in muscle. These results suggest that Ataxin-3 expression may play a protective role against enhanced endogenous oxidative stress due to reduced function of a number of antioxidant enzymes.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2010

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