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An examination of αB‐crystallin as a modifier of SOD1 aggregate pathology and toxicity in models of familial amyotrophic lateral sclerosis
Author(s) -
Karch Celeste M.,
Borchelt David R.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06572.x
Subject(s) - sod1 , amyotrophic lateral sclerosis , mutant , protein aggregation , spinal cord , microbiology and biotechnology , chaperone (clinical) , genetically modified mouse , crystallin , superoxide dismutase , biology , chemistry , transgene , biochemistry , pathology , neuroscience , medicine , disease , oxidative stress , gene
J. Neurochem. (2010) 113 , 1092–1100. 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 αB‐crystallin is capable of reducing aggregation of mutant SOD1. To test the role of αB‐crystallin in modulating SOD1 aggregation in vivo , αB‐crystallin deficient mice were bred to mice expressing two different SOD1 mutants (G37R and L126Z). Although completely eliminating αB‐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 αB‐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 αB‐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.