title: An examination of alpha B-crystallin as a modifier of SOD1 aggregate pathology and toxicity in models of familial amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis is a progressively paralytic neurodegenerative disease that can be caused by mutations in Cu,Zn-superoxide dismutase 1 (SOD1). Transgenic mice that over-express mutant SOD1 develop paralysis and accumulate aggregates of mutant protein in the brainstem and spinal cord. The present study uses a cell culture model to demonstrate alpha B-crystallin is capable of reducing aggregation of mutant SOD1. To test the role of alpha B-crystallin in modulating SOD1 aggregation in vivo, alpha B-crystallin deficient mice were bred to mice expressing two different SOD1 mutants (G37R and L126Z). Although completely eliminating alpha B-crystallin reduced the interval to disease endstage by 20-30 days in mice expressing either mutant, there were no detectable changes in the levels of sedimentable, SOD1 aggregates in the spinal cord of symptomatic mice. Because alpha B-crystallin is most abundantly expressed in muscle, we expected that the loss of this chaperone would leave this tissue vulnerable to mutant SOD1 aggregation. However, there was no evidence of mutant SOD1 aggregation in the muscle of mice lacking alpha B-crystallin. Our findings indicate that a significant perturbation to the protein homeostasis network of muscle is not sufficient to induce the aggregation of misfolded mutant SOD1. These outcomes have implications regarding the role of chaperones in modulating the tissue specific accumulations of misfolded SOD1.
authors.affiliation: Department of Neuroscience, McKnight Brain Institute, SantaFe HealthCare Alzheimer's Disease Research Center, University of Florida, Gainesville, Florida 32611, USA.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D002498:Centrifugation; D003902:Detergents; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000502:physiology; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000502:physiology*
chemical_list: D003902:Detergents; C000606290:SOD1 protein, human; D038203:alpha-Crystallin B Chain; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1