Abstract

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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS049134-07
Application #
8249453
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
7
Fiscal Year
2011
Total Cost
$105,110
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Sheng, Yuewei; Capri, Joseph; Waring, Alan et al. (2018) Exposure of Solvent-Inaccessible Regions in the Amyloidogenic Protein Human SOD1 Determined by Hydroxyl Radical Footprinting. J Am Soc Mass Spectrom :
Ayers, Jacob I; McMahon, Benjamin; Gill, Sabrina et al. (2017) Relationship between mutant Cu/Zn superoxide dismutase 1 maturation and inclusion formation in cell models. J Neurochem 140:140-150
Xu, Guilian; Fromholt, Susan; Ayers, Jacob I et al. (2015) Substantially elevating the levels of ?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
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
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
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
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

Showing the most recent 10 out of 56 publications