Modeling Mutant Profilin 1 Toxicity and ALS in vivo

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DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), is a fatal neurodegenerative disease that kills motor neurons, leading to paralysis and death. The mechanism of motor neuron degeneration is not understood and the disease is currently incurable. Ten percent of ALS cases are familial and ninety percent are sporadic. Numerous genetic mutations have been identified to cause familial ALS, which include mutations in SOD1, ALS2, VAPB, senataxin, dynactin, angiogenin, TDP-43, FUS, UBQLN2 and c9orf72 genes. By investigating the mechanism whereby these mutants cause neurodegeneration in cellular and animal models, advances have been made in our understanding of the disease mechanism. Recently, by years of genetic studies we have discovered novel mutations in the profilin1 gene that cause ALS. Profilin is an actin-binding protein involved in regulation of actin dynamics and other important cellular signaling processes. Our preliminary experiments in cultured cells suggest that the PFN1 mutants can form intracellular aggregates, dominantly disrupt actin polymerization and growth cone morphology, leading to an inhibition of axon outgrowth. Based on these observations, we hypothesize that mutant profilin 1 cause neurodegeneration by a gain-of-function type of mechanism. To test this hypothesis, we propose to construct and analyze transgenic mice that overexpress mutant and wild type profilin 1. The results will provide evidence either for or against this hypothesis. In addition, if overexpression of mutant profilin 1 causes motor neuron degeneration, this experiment will also generate a new mouse model for ALS, which can be used by the ALS research community to explore the mechanism of motor neuron degeneration and test therapeutic strategies.