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 ntultifactoral approach to determine the relationship between aggregation and disease progression.
Aim 2 will directiy 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.
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.
|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|
|Sheng, Yuewei; Abreu, Isabel A; Cabelli, Diane E et al. (2014) Superoxide dismutases and superoxide reductases. Chem Rev 114:3854-918|
|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 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|
Showing the most recent 10 out of 56 publications