Transgenic models of ALS caused by VAPB mutation

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DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes motor neuron degeneration, skeletal muscle atrophy, paralysis and death. Our long term objective is to understand the disease mechanism and develop a cure. At present, the only robust model for typical ALS is mice that express mutant SOD1. Recently, a mutation in VAMP associated protein B (VAPB) gene has been identified to cause motor neuron degeneration and ALS. The clinical symptom of ALS as a result of the VAPB mutation is variable and includes both typical and atypical cases. All, however, is adult onset. Based on in vitro data, the predominant hypothesis regarding the mechanism whereby mutant VAPB induces ALS is that the mutation leads to a dominant negative activity. However, no in vivo data is available. In addition, other possibilities, such as dominant gain-of-function and loss-of-function have not been ruled out. We propose to differentiate these three possibilities using transgenic approaches to overexpress the mutant VAPB and to silence the mouse VAPB using transgenic RNAi. The combined data from these two approaches will unequivocally determine which one of these three mechanisms is true. Because our transgenic constructs are designed to be Cre-inducible, these transgenic mice can be used to investigate the roles of mutant VAPB expression in motor neuron and non-motor neuron cells in the future by crossing with mice that express Cre in various specific cells (neurons, glia and microglia). Furthermore, we propose complementary experiments in cultured cells to dissect the function of VAPB and the altered function in mutant VAPB. These experiments will enhance our understanding of mechanisms of motor neuron degeneration and establish a second line of adult onset transgenic model for ALS, which can be used for preclinical analysis of therapeutic strategies for ALS. RELEVANCE: A VAPB gene mutation causes amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease without a cure. We propose to establish cell culture and transgenic mouse models to investigate how the VAPB mutation causes neuronal degeneration. Once established, these models can be used for pre-clinical tests of therapeutic compounds.