Transgenic mouse models of SODI-linked ALS show a number of similar phenotypes. First, all mice that express the mutant protein at high levels [>3 fold over endogenous) develop a progressive paralytic disease. Second, in the interval between the onset of symptoms and human endpoint, spinal cord tissues accumulate large, detergent-insoluble, aggregates of mutant SODl. Third, prior to the onset of symptoms, a number of pathologic abnormalities appear in spinal cord, including loss of muscle innervation, astrogliosis, and pathologic changes in motor neuron morphology. In the prior award period, we uncovered a link between the inherent ability of mutant SODl to form large, sedimentable, aggregates and the rate at which disease progresses in humans. For example the A4V mutation in SODl is associated with short duration disease and is highly prone to aggregate. By contrast the H46R mutation in SODl is associated with disease of long duration (>15 years) and is much less prone to form aggregates. In the present application, we propose 4 Aims that will clarify the role of mutant SODl aggregation, and/or multimerization, in that pathogenesis of ALS.
Aim 1 will directly follow up on studies of the first award period to further investigate the association between aggregation of mutant SODl and disease progression. We will determine whether all disease-associated mutations in SODl cause protein aggregation and use a multifactoral approach to determine the relationship between aggregation and disease progression.
Aim 2 will directly test the role of mutant SODl aggregation in disease progression by altering mutant protein aggregation in transgenic SODl mouse models. Multiple approaches will be used to manipulate aggregation of mutant SODl in mice.
Aim 3 will determine define the relationships between mutant SODl multimerization and the evolution of disease.
Aim 4 will seek to determine the mechanism by which co-expression of wild-type human SODl in mutant mice hastens the onset of disease. High level expression of wild-type SODl augments a toxicity that hastens the onset of disease and may affect the rate of disease progression. At the conclusion of these studies, we will have clarified the nature of SODl proteins that induce early disease phenotypes and determined the role of mutant SODl multimerization in disease progression.

Public Health Relevance

The advances made by this Project over the past five years have significantly increased our understanding of the disease process in the ALS-transgenic mouse models, particularly the role of S0D1 aggregation as a modulator of disease progression. The studies proposed here, as a component of the overall project, have the potential to define biophysical aspects of S0D1 aggregation that cause motor neuron disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Ming, Li-June; Valentine, Joan Selverstone (2014) Insights into SOD1-linked amyotrophic lateral sclerosis from NMR studies of Ni(2+)- and other metal-ion-substituted wild-type copper-zinc superoxide dismutases. J Biol Inorg Chem 19:647-57
Brown, Hilda H; Borchelt, David R (2014) Analysis of mutant SOD1 electrophoretic mobility by Blue Native gel electrophoresis; evidence for soluble multimeric assemblies. PLoS One 9:e104583
Ayers, Jacob; Lelie, Herman; Workman, Aron et al. (2014) Distinctive features of the D101N and D101G variants of superoxide dismutase 1; two mutations that produce rapidly progressing motor neuron disease. J Neurochem 128:305-14
Ivanova, Magdalena I; Sievers, Stuart A; Guenther, Elizabeth L et al. (2014) Aggregation-triggering segments of SOD1 fibril formation support a common pathway for familial and sporadic ALS. Proc Natl Acad Sci U S A 111:197-201
Sheng, Yuewei; Abreu, Isabel A; Cabelli, Diane E et al. (2014) Superoxide dismutases and superoxide reductases. Chem Rev 114:3854-918
Ayers, Jacob I; Xu, Guilian; Pletnikova, Olga et al. (2014) Conformational specificity of the C4F6 SOD1 antibody; low frequency of reactivity in sporadic ALS cases. Acta Neuropathol Commun 2:55
Chan, Pik K; Chattopadhyay, Madhuri; Sharma, Shivani et al. (2013) Structural similarity of wild-type and ALS-mutant superoxide dismutase-1 fibrils using limited proteolysis and atomic force microscopy. Proc Natl Acad Sci U S A 110:10934-9
Rutherford, Nicola J; Lewis, Jada; Clippinger, Amy K et al. (2013) Unbiased screen reveals ubiquilin-1 and -2 highly associated with huntingtin inclusions. Brain Res 1524:62-73
Prudencio, Mercedes; Lelie, Herman; Brown, Hilda H et al. (2012) A novel variant of human superoxide dismutase 1 harboring amyotrophic lateral sclerosis-associated and experimental mutations in metal-binding residues and free cysteines lacks toxicity in vivo. J Neurochem 121:475-85
Lelie, Herman L; Liba, Amir; Bourassa, Megan W et al. (2011) Copper and zinc metallation status of copper-zinc superoxide dismutase from amyotrophic lateral sclerosis transgenic mice. J Biol Chem 286:2795-806

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