While proteasome inhibitors are an effective cancer treatment option, the idea of accelerating the activity of the proteasome for medical purposes represents a novel treatment option for neurological disorders where harmful proteins accumulate and cause disease. Chronic neurological diseases such as Parkinson's, Alzheimer's, Huntington's, Frontotemporal dementia and Spinocerebellar ataxias are characterized by the presence of ubiquitinated protein aggregates and reduced proteasome function. Therefore, while these mutant proteins can be targeted for proteasomal degradation, they are not effectively eliminated by the ubiquitin proteasome system. We recently determined that either genetic or pharmacological inhibition of the ubiquitin hydrolase activity of Usp14 is sufficient to accelerate protein degradation by the proteasome. The levels of several proteins, including tau, TDP-43 and ataxin-3, were significantly decreased following the inhibition of Usp14's ubiquitin- hydrolase activity, indicating that Usp14 can function as an inhibitor of the proteasome. Our working hypothesis is that Usp14 functions to edit the ubiquitin side chains of proteins prior to their commitment to proteasomal degradation, resulting in release of the substrate from the proteasome. The focus of this proposal is to determine if loss of Usp14's ubiquitin hydrolase-activity can reduce the levels of aggregate- prone proteins produced in animal models of Huntington's disease, Frontotemporal dementia and Parkinson's disease. This novel approach to enhancing proteasome function for the clearance of aggregate- prone proteins may lead to a powerful new treatment option for patients suffering from chronic neurological diseases.

Public Health Relevance

The ubiquitin proteasome system functions to remove damaged and misfolded proteins within cells. Since many chronic neurological disorders show impaired protein degradation and protein accumulation, strategies designed to enhance proteasome activity offer provide a novel therapeutic intervention for the clearance of toxic proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS074456-02
Application #
8325007
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$183,125
Indirect Cost
$58,125
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Hallengren, Jada J; Vaden, Ryan J (2014) Sodium-potassium ATPase emerges as a player in hippocampal phenotypes of Angelman syndrome mice. J Neurophysiol 112:5-8
Hallengren, Jada; Chen, Ping-Chung; Wilson, Scott M (2013) Neuronal ubiquitin homeostasis. Cell Biochem Biophys 67:67-73