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Interaction between Familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 Mutants and the Dynein Complex

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron death. More than 90 mutations in the copper-zinc superoxide dismutase (SOD1) gene cause a subset of familial ALS. Toxic properties have been proposed for the ALS-linked SOD1 mutants, but the...

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Published in:The Journal of biological chemistry 2007-06, Vol.282 (22), p.16691-16699
Main Authors: Zhang, Fujian, Ström, Anna-Lena, Fukada, Kei, Lee, Sangmook, Hayward, Lawrence J., Zhu, Haining
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container_end_page 16699
container_issue 22
container_start_page 16691
container_title The Journal of biological chemistry
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creator Zhang, Fujian
Ström, Anna-Lena
Fukada, Kei
Lee, Sangmook
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description Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron death. More than 90 mutations in the copper-zinc superoxide dismutase (SOD1) gene cause a subset of familial ALS. Toxic properties have been proposed for the ALS-linked SOD1 mutants, but the nature of the toxicity has not been clearly specified. Cytoplasmic inclusion bodies containing mutant SOD1 and a number of other proteins are a pathological hallmark of mutant SOD1-mediated familial ALS, but whether such aggregates are toxic to motor neurons remains unclear. In this study, we identified a dynein subunit as a component of the mutant SOD1-containing high molecular weight complexes using proteomic techniques. We further demonstrated interaction and colocalization between dynein and mutant SOD1, but not normal SOD1, in cultured cells and also in G93A and G85R transgenic rodent tissues. Moreover, the interaction occurred early, prior to the onset of symptoms in the ALS animal models and increased over the disease progression. Motor neurons with long axons are particularly susceptible to defects in axonal transport. Our results demonstrate a direct “gain-of-interaction” between mutant SOD1 and dynein, which may provide insights into the mechanism by which mutant SOD1 could contribute to a defect in retrograde axonal transport or other dynein functions. The aberrant interaction is potentially critical to the formation of mutant SOD1 aggregates as well as the toxic cascades leading to motor neuron degeneration in ALS.
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More than 90 mutations in the copper-zinc superoxide dismutase (SOD1) gene cause a subset of familial ALS. Toxic properties have been proposed for the ALS-linked SOD1 mutants, but the nature of the toxicity has not been clearly specified. Cytoplasmic inclusion bodies containing mutant SOD1 and a number of other proteins are a pathological hallmark of mutant SOD1-mediated familial ALS, but whether such aggregates are toxic to motor neurons remains unclear. In this study, we identified a dynein subunit as a component of the mutant SOD1-containing high molecular weight complexes using proteomic techniques. We further demonstrated interaction and colocalization between dynein and mutant SOD1, but not normal SOD1, in cultured cells and also in G93A and G85R transgenic rodent tissues. Moreover, the interaction occurred early, prior to the onset of symptoms in the ALS animal models and increased over the disease progression. Motor neurons with long axons are particularly susceptible to defects in axonal transport. Our results demonstrate a direct “gain-of-interaction” between mutant SOD1 and dynein, which may provide insights into the mechanism by which mutant SOD1 could contribute to a defect in retrograde axonal transport or other dynein functions. 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subjects Amyotrophic Lateral Sclerosis - enzymology
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - pathology
Animals
Axonal Transport - genetics
Axons - enzymology
Axons - pathology
Cell Line
Disease Models, Animal
Dyneins - genetics
Dyneins - metabolism
Genetic Diseases, Inborn - enzymology
Genetic Diseases, Inborn - genetics
Genetic Diseases, Inborn - pathology
Humans
Inclusion Bodies - enzymology
Inclusion Bodies - genetics
Inclusion Bodies - pathology
Mice
Motor Neurons - enzymology
Motor Neurons - pathology
Multienzyme Complexes - genetics
Multienzyme Complexes - metabolism
Mutation
Protein Binding - genetics
Proteomics
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Superoxide Dismutase-1
title Interaction between Familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 Mutants and the Dynein Complex
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