Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease. ALS is clinically characterized by the degeneration of motor neurons in the brain and spinal cord, culminating in paralysis and death within 1-5 years. Presently, there is no cure for ALS. Mutations in the gene encoding superoxide dismutase (SOD1) cause familial, or inheritable, ALS (FALS). FALS constitutes 10% of ALS cases, whereas the remaining 90% are sporadic in nature (SALS). Although SALS and FALS are clinically indistinguishable, the causative factor(s) associated with SALS are unknown. More than 150 mutations in the SOD1 gene have been linked to FALS, and yet it is still undetermined whether the wild-type (WT) form of SOD1 plays a role in sporadic ALS. The overall goal of this proposal is to test the hypothesis that altered modifications of SOD1 WT are implicated as causative factors in SALS. We have designed our experimental approach to address four criteria that in our view must be fulfilled to define a causal role for SOD1 WT in SALS: detection of modified SOD1 WT in SALS specimens (Aims 1, 2 and 3);relevance of modified SOD1 WT to pathogenic pathways in the disease (Aims 4 and 5);an appropriate dose response relationship between modified SOD1 WT and severity of disease (Aims 2 and 5);and demonstration that modified SOD1 WT can propagate the disease in normal hosts or cells (Aim 5). These experiments have the potential to significantly impact ALS research, by defining disease mechanisms and by identifying therapeutic targets.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease. While 10% of ALS cases are familial or inherited, the vast majority (90%) are sporadic (SALS). Mutations in superoxide dismutase (SOD1) have been identified as the most common cause of FALS. However, the origins of SALS have not been identified, nor is it known if wild-type (WT) SOD1 is involved in SALS. The goal of this proposal is to further test the hypothesis that altered modifications of WT SOD1 are implicated as causative factors in SALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gubitz, Amelie
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University of Massachusetts Medical School Worcester
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