The accumulation of ubiquitin-immuno-reactive material in cell bodies, dendrites, and/or axons of neurons are a prevalent pathology of neurodegenerative disease. It has been suggested that the accumulation of this material is a cellular symptom of reduced ubiquitin/proteasome system (UPS) function. In the present application, we propose four Aims that are designed to probe whether and how the proteasome/ubiquitin system is dysfunctional in various models of neurodegenerative disease.
In Aim 1, we propose to use genetic approaches to alter the activities of UPS components. We have been provided mice lacking parkin (a biquitin E3 ligase whose loss triggers Parkinson's disease), and we would like to cross these mice to our APPswe/PS1dE9 mice. We hypothesize that amyloid deposition, in a context of parkin deficiency, may induce novel cytoplasmic pathologies, such as Lewy-body-like inclusions.
Aim 2 will develop systems to inhibit proteasome function in vivo in transgenic mice, both chronically and acutely, using genetic approaches.
Aim 3 will build on recent characterization of a subset of sporadic ALS cases, where we have identified cystatin C as a protein of interest in the disease. To test the role of this protein in ALS, we propose to create transgenic animals that express elevated levels of the human protein.
Aim 4 will focus on identifying the protein backbone constituents of the ubiquitin immunoreactive material that accumulates in our mouse models of Alzheimer's disease and ALS.
This Aim will involve the development of transgenic mice expressing recombinant ubiquitin molecules carrying peptide motifs that facilitate detection and purification. Collectively, these studies should allow us to examine the role of proteasome dysfunction in disease pathogenesis and perhaps identify some of the mis-folded proteins that accumulate in disease-associated inclusions. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044278-04
Application #
7052792
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Murphy, Diane
Project Start
2004-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$332,288
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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