Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with both sporadic and familial forms. Mutations in the copper-zinc superoxide dismutase gene (SOD1) account for 10 to 20 percent of inherited ALS. Over 100 different mutations in SOD1 can cause ALS. At least eight of these have been shown to produce an ALS-like phenotype when expressed in transgenic mice. We previously found that the expression of the ALS in one of these mutants, murine G86R (mG86R) SOD1 is highly dependent upon the strain background: in the FVB/N background the mG86R SOD1 mice develop ALS at an average of 103 days while in a mixed background of (FVB/N x 129Sv/C57BI6) ALS develops at an average of 211 days. We have mapped three modifier loci that have modest effects on ALS onset when inherited individually. However, two of the three loci can interact synergistically to produce greatly extended life spans. We have localized one of the modifiers from the 129Sv strain to a single bacterial artificial chromosome (BAC) containing just four genes. Transgenic mice carrying this BAC, 149m19, have a modest 13 day increase in mean survival that is similar to the protection conferred by the ALS drug riluzole in similar transgenic lines. There are three major goals of this proposal: (1) to identify the specific gene on 149m19 BAC that is responsible for delaying ALS onset in our mouse model; (2) to refine the location of the two synergistic modifier loci on chromosomes 5 and 13 and (3) to identify the specific protective genes contained within the chromosome 5 and 13 regions. Although SOD1 was identified as an ALS causative gene in 1993, it is still unclear how mutations in this protein cause disease. The identification of the modifier genes and the polymorphisms within them that decrease the toxicity of mutant SOD1 should give insight into the pathogenic mechanism SOD1. Ideally, the discovery of the modifying genes and their mechanism(s) of action will lead to as yet unidentified targets for pharmacological intervention for ALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041646-08
Application #
7230479
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Refolo, Lorenzo
Project Start
2001-05-15
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
8
Fiscal Year
2007
Total Cost
$337,890
Indirect Cost
Name
University of Denver
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
007431760
City
Denver
State
CO
Country
United States
Zip Code
80208
Hasselmo, Michael E; Stern, Chantal E (2006) Mechanisms underlying working memory for novel information. Trends Cogn Sci 10:487-93
Kunst, Catherine B (2004) Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet 75:933-47