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Alpha-Tubulin Mutation and Motor Neuron Disease

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PROJECT SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease, is a fatal disease resulting from progressive degeneration of motor neurons and affects ~30,000 American each year. Currently, the mechanisms responsible for motor neuron death in ALS are not fully understood and there is no effective therapy to cure or slow the progression of this inexorable disease. The recent discovery of TUBA4A mutations in familial ALS patients added a new gene with implication in cytoskeleton dynamics in motor neurons. We became highly interested to investigate the role of mutant ?-tubulin in the cytoskeleton dynamics and defects in ALS. Toward that end, we have planned to generate novel transgenic mice overexpressing mutant human wildtype and mutant ?-tubulin. Our long-term goal is to understand the mutant ?-tubulin neurotoxicity in motor neuron degeneration and develop strategy to block its toxicity. Our immediate goal is to construct, develop a novel animal model that bears a mutation identical to that found in multiple families with ALS. We hypothesize that the overexpression of mutant ?-tubulin protein in mice will result in development of cardinal phenotypes and pathologies that resemble those in ALS patients. The first aim is to generate ?-tubulin transgenic mice and assess for progressive motor deficits and phenotypes resembling ALS. Adult mice will be studied for signs and symptoms that attributes to functional motor neuron degeneration, correlating the severity of the dysfunction to TUBA4A transgene copy number, protein expression level, and protein activity. The second aim is to characterize hTUBA4AR320C and hTUBA4AWT transgenic mice and compare neuromuscular pathologies with those of SOD1G93A and our recent hPFN1G118V transgenic mice. Brain, spinal cord and skeletal muscle tissues will be studied to determine pathological anomalies including damage to neuronal loss, axonal damage, production of oxidative stress, and glial activation. Microtubule polymerization and a-tubulin activity assays will be performed to determine if the R320C mutation disrupts the structure of the microtubule. The impact of this work could be highly significant for its potential in creating a new animal model for research areas complementary to existing ALS research. This study will provide a new tool to determine the central importance of mutant ?-tubulin as a basic mechanism that may contribute to the neurodegeneration found in ALS patients. We expect that this mouse model may also facilitate development of therapeutic strategies for ALS. Thus, the results are expected to have a significant impact because our model may provide new targets for discovery of basic mechanisms and therapies to prevent or stop progression of ALS-associated neurodegeneration.

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