This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.a-synuclein was the first gene identified as causing a familial form of Parkinson's disease. It is also associated with sporadic forms of the disease in that a-synuclein protein is a major component of Lewy bodies, the pathologic hallmark of Parkinson's. Mice overexpressing mutant human a-synuclein have been generated in attempts to develop mouse models of the human disease. Use of heterologous promoters such as the prion promoter have led to overexpression in spinal cord, leading to a lethal motor neuron disease (Cabin et al., 2005). This disease, while not recapitulating Parkinson's disease, provides a useful model for investigating the mechanism of a-synuclein toxicity. Motor neuron function is required for viability in mouse. In the motor neuron synucleinopathy, Wallerian degeneration occurs prior to degeneration of neuronal cell bodies (Cabin et al., submitted). Degeneration of sciatic nerve axons in these mice provides an accessible system in which to examine how a-synuclein causes disease. Results from this system should be applicable to axonal degeneration in early stages of Parkinson's disease. However, in order to develop a mouse model of Parkinson's that better recapitulates the human disease, we are using transgenic mice in which mutant human a-synuclein is regulated by its endogenous promoter. This should ensure appropriate expression of the transgene so that artifactual synucleinopathies should not arise. Parkinson's disease affects many regions of the human nervous system besides the dopaminergic neurons of the substantia nigra. The earliest effects are on the olfactory and enteric nervous systems. These early stages cannot be studied in humans, illustrating the importance of a good mammalian model system. Another aspect of our work is to determine the normal function of a-synuclein. Without understanding the normal function, we cannot know if loss of that function might contribute to neurological disease. We are taking genetic approaches to this problem, with an ENU sensitization screen to identify genes in the same or parallel pathways, and mutational analysis of the protein itself. In addition, we hope to understand its importance during oxidative stress by examining the transcriptome of both WT and a-synuclein null mice after stressing with the herbicide paraquat.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015583-09
Application #
7720408
Study Section
Special Emphasis Panel (ZRR1-RI-8 (02))
Project Start
2008-05-01
Project End
2009-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
9
Fiscal Year
2008
Total Cost
$182,085
Indirect Cost
Name
University of Montana
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
010379790
City
Missoula
State
MT
Country
United States
Zip Code
59812
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