Cu/Zn superoxide dismutase (SOD1) mutations cause about 20 percent of cases of familial amyotrophic lateral sclerosis (FALS). Transgenic mice expressing mutant SOD1 develop a progressive motor neuron disease. A long term goal is to understand the molecular mechanisms by which SOD1 mutants cause selective motor neuron degeneration. Copper, an essential cofactor for SOD1 enzymatic activity, has been proposed to play a critical role in the pathogenesis of SOD1-linked ALS. Because free copper can be toxic in cells, the delivery of copper to specific proteins within various compartments of the cell is tightly regulated by specific copper chaperones like CCS. Previous efforts have demonstrated that CCS is necessary to deliver copper to SOD1, and CCS-deficient mice are viable and show no SOD1 activity. First, to test whether Cu in mutant SOD1 is required to cause motor neuron degeneration, CCS-deficient mice will be crossbred with a series of mutant SOD1 mice. If Cu participates in killing motor neurons, mutant SOD1 mice without CCS will show significant amelioration or rescue of motor neuron disease. Second, because 30 percent of SOD1 is not charged with Cu, transgenic mice overexpressing CCS will be generated to examine whether the level of active SOD1 can be increased in vivo by elevating the level of CCS. Finally, to determine the domains of CCS that are important for Cu delivery, a series of mutant CCS DNA constructs will be transfected into wild-type and CCS-deficient cells to identify CCS mutants that are able to inhibit the CCS Cu trafficking pathway. Taken together, these efforts will test Cu-based neurotoxicity mechanisms in vivo. The results will have the potential to identify novel therapeutic targets and may have implications for the design of drug treatments for motor neuron disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS040014-01
Application #
6089983
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Heemskerk, Jill E
Project Start
2000-04-10
Project End
2005-03-31
Budget Start
2000-04-10
Budget End
2001-03-31
Support Year
1
Fiscal Year
2000
Total Cost
$286,344
Indirect Cost
Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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