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Description
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Spinal muscular atrophy (SMA) is a disease characterized by the progressive degeneration of spinal cord motor neurons (MNs). Smn1, the gene responsible for SMA, has been extensively studied, but the molecular mechanisms underlying MNs death are still elusive and treatments for the disease have not been found. We propose the use of C.elegans as a pre-clinical model system to define new therapeutic options. We want to identify new conserved molecular drug targets and innovative compounds that modulate SMN function and rescue neuronal death. Pathways involving SMN are conserved and C.elegans presents many experimental advantages. We will devise effective drug discovery in a whole-animal and elucidate some of the molecular basis of SMA. Using a modification of RNAi we silenced ceSmn1 only in a subclass of MNs. We observed neuronal death and homologs of Smn1 modulators genetically interacts with ceSmn1 for this function. Valproic Acid partially reverts this phenotype. Our results provide strong evidence that this is a powerful and unique tool to study SMA, that allows both the study of the neurodegeneration process in vivo and the test of new therapeutics. We will use genetic manipulations, drug treatments and phenotypic analysis to identify genetic and chemical modifiers of SMN function, strictly focussing on the correction of neuron death. In AIM1 we will identify and characterize proteins that interact with ceSMN1 and that, once lost, prevent neurodegeneration. In AIM2 we will challenge our model with drugs and evaluate their ability to restore neuronal survival, and positive hits will be tested on mouse cell cultures. We expect to deliver major progress in defining new therapeutic strategies for preventing neuronal death. This approach represents a powerful and effective strategy for biomedical research and data gathered in the research project will be translated into mammalian models to refine future strategies for restoring SMN functionality in SMA patients |
