Off-campus University of Miami users: To download campus access theses, please use the following link to log into our proxy server with your University of Miami CaneID and Password.

Non-University of Miami users: Please talk to your librarian about requesting this thesis through interlibrary loan.

Publication Date

2011-05-03

Availability

UM campus only

Embargo Period

2011-05-03

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Neuroscience (Medicine)

Date of Defense

2011-04-26

First Committee Member

Michael Kim

Second Committee Member

Jeffrey Goldberg

Third Committee Member

Grace Zhai

Fourth Committee Member

Julia Dallman

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the progressive degeneration of motor neurons. Although there has been some progress in the identification of genes linked to inherited cases of ALS, the etiology of this disease remains largely unknown. Clinical progression of motor neuron diseases is associated with the degeneration of the axon preceding cell death. Elucidating novel mechanisms important for motor axon maintenance will help gain greater insight into disease pathogenesis. Here, I report that mutations in ras-opposite (rop), which encodes the Drosophila homologue of mammalian Sec1/Munc18, cause progressive degeneration of motor axons while sensory axons are largely unaffected. While mutations in mammalian munc18-1 have been linked to degeneration of the spinal cord, the mechanisms by which this occurs are unknown. Using Drosophila, I found that RNAi-induced knockdown of rop leads to severe motor deficits in adult flies. In addition, I discovered that motor axon degeneration in rop mutants could be delayed by overexpression of the neuronal maintenance factor Nmnat. Interestingly, I found that Rop is localized with Nmnat at the neuromuscular junction and that Rop physically interacts with Nmnat in vivo. These data indicate a novel role for Rop in motor axon maintenance and provide insight into the pathogenesis of neurodegenerative diseases targeting motor neurons, such as ALS.

Keywords

Rop; Munc18; ALS; neurodegeneration; Drosophila; motor neurons

Download

Share

COinS