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.
|Ayers, Jacob I; McMahon, Benjamin; Gill, Sabrina et al. (2016) Relationship between mutant SOD1 maturation and inclusion formation in cell models. J Neurochem :|
|Xu, Guilian; Fromholt, Susan; Ayers, Jacob I et al. (2015) Substantially elevating the levels of Î±B-crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation. J Neurochem 133:452-64|
|Gelfand, Paul; Smith, Randy J; Stavitski, Eli et al. (2015) Characterization of Protein Structural Changes in Living Cells Using Time-Lapsed FTIR Imaging. Anal Chem 87:6025-31|
|Chattopadhyay, Madhuri; Nwadibia, Ekeoma; Strong, Cynthia D et al. (2015) The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation. J Biol Chem 290:30624-36|
|Xu, Guilian; Ayers, Jacob I; Roberts, Brittany L et al. (2015) Direct and indirect mechanisms for wild-type SOD1 to enhance the toxicity of mutant SOD1 in bigenic transgenic mice. Hum Mol Genet 24:1019-35|
|Saelices, Lorena; Johnson, Lisa M; Liang, Wilson Y et al. (2015) Uncovering the Mechanism of Aggregation of Human Transthyretin. J Biol Chem 290:28932-43|
|Bourassa, Megan W; Brown, Hilda H; Borchelt, David R et al. (2014) Metal-deficient aggregates and diminished copper found in cells expressing SOD1 mutations that cause ALS. Front Aging Neurosci 6:110|
|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|
|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|
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