All ETDs from UAB

Advisory Committee Chair

Scott M Wilson

Advisory Committee Members

Robin Lester

Farah Lubin

Lori L McMahon

David Standaert

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The ubiquitin proteasome system (UPS) plays a critical role in regulating a diversity of cellular processes that are essential to neuronal function, such as synaptic transmission, axon guidance, and neurite outgrowth. Dysfunctions of the UPS are linked with many neurodegenerative disorders, including motor neuron diseases like spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), although it is not known how UPS dysfunction contributes to disease pathology. The proteasome, an approximate 2.5 megadalton protein complex comprised of a 20S core particle and 19S regulatory particle, is the site of ubiquitin-mediated proteolysis in the cell. Recent studies have linked ubiquitin specific protease 14 (USP14), a deubiquitinating enzyme associated with the 19S regulatory particle, with synaptic transmission at the neuromuscular junction (NMJ) and in the hippocampus. The studies presented in this thesis focus on expanding the understanding of the role of USP14 in the development and function of the nervous system through the analysis of a mouse model of USP14 dysfunction, nmf375. In this study, we show that the phenotypic consequences of the loss of USP14 are largely dependent upon genetic background. nmf375 mice harbor a mutation in Usp14 that reduces USP14 protein levels by 95%. Previous studies on the role of USP14 in the nervous system indicate that a protein loss of this magnitude leads to a neurodevelopmental phenotype. Surprisingly, nmf375 mice develop adult-onset neuromuscular disease. These studies reveal that the BALB/c background is less susceptible than the C57 background to the structural and functional deficits in synaptic transmission that are caused by the loss of USP14, separate the functional from the structural deficits at the NMJ caused by USP14 deficiency, and show that USP14 is critical for the maintenance of adult NMJs. The data presented here suggests the presence of a genetic suppressor present on the BALB/c background that can partially compensate for the function of USP14 in development.

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