This item is accessible only to the Washington University community.

Off-Campus WUSTL Users: Click the “Off-Campus Download” button below. You will be prompted to log in using your WUSTL Key.

Date of Award

Spring 2011

Author's School

College of Arts & Sciences

Author's Department/Program

Biology

Abstract

Axon degeneration is a process that occurs during many neurodegenerative diseases, leading to motor dysfunction, cognitive impairments, and lack of bodily control. Axons can degenerate from a variety of different catalysts such as acute injury, protein aggregation, and drugs, to name a few. Whether the mechanism of degeneration is standard among different injuries is largely unknown. Wallerian degeneration, the defined cascade of events from injury to axon demise distal to the site of injury, induces cellular problems relating to transport through the axon, mitochondrial dysfunction, calcium concentration levels, and membrane fragmentation. There was a molecule discovered that seems to protect against multiple insults, suggesting that the degenerative pathway has conserved components. We performed a forward genetic screen in D. melanogaster to identify molecules that protect against degeneration when knocked down or overexpressed, as any identified could inform treatment strategies for a variety of neurodegenerative diseases. We induced degeneration with paclitaxel, a chemotherapy drug that disrupts microtubule dynamics and induces peripheral neuropathy. To see neurodegeneration, we looked at the microtubule architecture and neuronal membranes in the entire nervous system, as well as a tagged subset of sensory neurons in transgenic flies. We found genes that show both more intact axons and dendrites when certain genes are knocked down or over expressed. A few genes discovered to be protective from the screen are genes that have been implicated in dendrite pruning in the scientific literature. Upon further research, we discovered that many of the processes thought to be involved in neurodegeneration are also used in dendrite pruning, such as microtubule destabilization, branch severing, retraction, and debris clearance. I researched the connection between dendrite pruning and neurodegeneration, hypothesizing that the there are elements in the pathway present in both mechanisms. I tested more specific pruning genes in the degeneration assay and looked at whether any genes from the screen may be involved in dendrite pruning. I identified a number of dendrite pruning genes required for axon degeneration, confirming my hypothesis about the conservation of mechanism. Since dendrite pruning is better characterized than neurodegeneration, further analysis could lead to a better understanding of the mechanisms of neurodegeneration.

Language

English (en)

Advisor/Committee Chair

Aaron DiAntonio

Second Advisor

Martha Bhattacharya