In this project, we elect to explore the role of gene/environment interaction by looking at environment not as the repository of noxious factors, but as the vector of complex inanimate and social stimulations. Our hypothesis is that an enriched environment incorporating social interactions, learning, and exercise modulates the effects of genetic risk factors and pathogenic mutations on the natural history of ALS. To test this hypothesis, we will use transgenic mice expressing the glycine-93 --> arginine mutant copper/zinc superoxide dismutase (SOD1G93A), a recognized model of inherited ALS, and well-validated conditions of enriched environment, which have been shown to be beneficial to a variety of pathological situations affecting the adult nervous system.
Specific Aim (SA)-I will evaluate the effect of such an enriched environment on the clinical expression of the disease in transgenic SOD1G93A mice. We will determine whether transgenic SOD1G93A mice exposed to an enriched environment become symptomatic later and survive longer than their counterparts exposed to a standard environment. SA-II will elucidate the anatomical correlates of the effects provided by this enriched environment in transgenic SOD1G93A mice. Here, the status of the lower motor neuron pathway and the magnitude of the glial reaction will be compared among transgenic SOD1G93A mice exposed to different environmental conditions. SA-III will investigate the molecular basis of the effects provided by this enriched environment in transgenic SOD1G93A mice. As a first step toward this goal, protein expression profiles in spinal cords from transgenic SOD1G93A mice exposed to the different environmental conditions will be compared using proteomic approaches. This development/exploratory project offers an high-risk/high-yield set of studies which may demonstrate, in an original way, how environment may impact on the occurrence and the progression of ALS.
| Banerjee, Rebecca; Mosley, R Lee; Reynolds, Ashley D et al. (2008) Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One 3:e2740 |
| Benner, Eric J; Banerjee, Rebecca; Reynolds, Ashley D et al. (2008) Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One 3:e1376 |
| Zhou, Chun; Huang, Yong; Shao, Yufang et al. (2008) The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci U S A 105:12022-7 |
| Andres-Mateos, Eva; Perier, Celine; Zhang, Li et al. (2007) DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci U S A 104:14807-12 |
| Nagai, Makiko; Re, Diane B; Nagata, Tetsuya et al. (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615-22 |
| Whittle, A J; Ross, O A; Naini, A et al. (2007) Pathogenic Lrrk2 substitutions and Amyotrophic lateral sclerosis. J Neural Transm 114:327-9 |
| Almer, Gabriele; Kikuchi, Hitoshi; Teismann, Peter et al. (2006) Is prostaglandin E(2) a pathogenic factor in amyotrophic lateral sclerosis? Ann Neurol 59:980-3 |
| Wu, Du-Chu; Re, Diane Berangere; Nagai, Makiko et al. (2006) The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Natl Acad Sci U S A 103:12132-7 |
| Bove, Jordi; Zhou, Chun; Jackson-Lewis, Vernice et al. (2006) Proteasome inhibition and Parkinson's disease modeling. Ann Neurol 60:260-4 |
| Kikuchi, Hitoshi; Almer, Gabriele; Yamashita, Satoshi et al. (2006) Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci U S A 103:6025-30 |
