Structural and biochemical methods will be used to characterize amyloid-Uke fibrils of SODl and its segments. The overall goals are to understand the process of fibrillation of SODl in vitro and in cells, and to determine atomic structures for the fibril-defining segments of SODl. This informatin will be used in the process of structure-based design, to create inhibitors of fibrillation of SODl and its mutants. These inhibitors can be lead compounds for drugs against SODl fibrillation and possibly fALS. A high-risk goal is to characterize the structure of SODl aggregates that form in human cells [see Project 3). In particular, micro-X-ray diffraction will be used to assess the possibility that SODl is in the amyloid state in cells.
for the Program as a whole is to provide structural information on the various fibrillar constructs produced in Projects 1,2, and 3. The wider relevance is to learn the structure of aggregated S0D1 in cells, and to design inhibititors of S0D1 aggregation, in the expectation that these can become lead compounds for drug discovery for ALS.
|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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