Researchers from College of Medicine detail new studies and findings in the area of amyotrophic lateral sclerosis genetics

2007 JUL 2 - (NewsRx.com) -- A new study, "Interaction between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the dynein complex," is now available. "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," investigators in the United States report.

"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," wrote F. Zhang and colleagues, College of Medicine.

The researchers concluded: "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."

Zhang and colleagues published their study in the Journal of Biological Chemistry (Interaction between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the dynein complex. Journal of Biological Chemistry, 2007;282(22):16691-9).

For additional information, contact F. Zhang, Graduate Center for Nutritional Sciences, Dept. of Molecular and Cellular Biochemistry, College of Medicine, Lexington, Kentucky 40536 USA.

The publisher of the Journal of Biological Chemistry can be contacted at: American Society Biochemistry Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814-3996, USA.

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