The ubiquitin-proteasome system (UPS) is a central pathway common to all eukaryotic cells for regulating protein turnover. There are numerous regulatory pathways that rely on the timely removal of critical proteins. These pathways include the cell cycle, DNA repair, receptor-mediated endocytosis and the induction of long-term memory. The inability to remove unwanted proteins from cells has been linked to several chronic neurological diseases including Parkinson's disease, Alzheimer's disease, and the Spinocerebellar ataxias. While it is clear that these diseases are associated with polyubiquitinated protein aggregates, it is not clear how these aggregates contribute to neuronal dysfunction. In contrast to the polyubiquitination signal that targets proteins for proteasomal degradation, a monoubiquintin tag can signal receptor internalization and sorting of intracellular vesicles. This modification by monoubiquitin is reversible and, akin to phosphorylation, can regulate protein localization and activity. We have recently demonstrated that Uspl4, a deubiquitinating enzyme (DUB) that specifically removes ubiquitin from proteins, is mutated in the neurological mouse mutant ataxia (ax/j). The axJ mice do not show protein aggregation defects or neuronal loss. Instead, these mice exhibit defects in synaptic transmission, indicating that neurological disease may be rooted in synaptic dysfunction. Our working hypothesis is that loss of Uspl4 disrupts the ubiquitinated state of specific components of the neurotransmitter release machinery, thereby resulting in synaptic defects. This proposal is therefore directed at addressing the role of Uspl4 in regulating synaptic function.
The first Aim will determine if Usp 14 associates with the 26S proteasome in neurons and if it has a role in ubiquitin-dependent proteolysis. In the second Aim, we will identify components and pathways that are regulated by Usp14 in order to better understand the regulation of ubiquitin modification in normal physiology and disease. The third Specific Aim will determine which neuronal circuits are disrupted by the loss of Uspl4 and examine how these circuits contribute to the tremor, ataxia and muscle wasting phenotypes of the ax J mice. Completion of these Specific Aims will enable us to uncover new processes that rely on ubiquitin-signaling and to determine how alterations in these pathways can lead to neurological disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BDCN-3 (01))
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Sutherland, Margaret L
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University of Alabama Birmingham
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