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Description
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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. The identification of new modifiers of SMN function will provide new targets for treatments. The identification of such modifiers would require a detailed knowledge of the SMN pathway, which may need decades of research and a lot of money. The use of the invertebrate C.elegans as a model for SMA provides: a) a powerful and rapid system to directly assess the consequences of mutations in rescuing ceSmn1 loss at the organismal level; b) the unique advantage in the analysis of neurodegenerative processes allowing visualization of individual neurons in living worm; c) less ethical concerns to the public. Indeed, according to B. Alberts (Alberts, Science 2010): “As incredible as it seems, future research on flies and worms will quite often provide the shortest and most efficient path to curing human disease.” In fact pathways involving SMN are conserved and C.elegans presents many experimental advantages. We are devising effective drug discovery in a whole-animal and elucidating 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 (Gallotta et al., HMG 2016). 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 are therefore using genetic manipulations, drug treatments and phenotypic analysis to identify genetic and chemical modifiers of SMN function, strictly focussing on the correction of neuron death. As first aim we want to identify and characterize proteins that interact with ceSMN1 and that, once lost, prevent neurodegeneration. . To this end we will need many plasmids (specific for C.elegans) from Addgene. As second aim, we will challenge our model with drugs and evaluate their ability to restore neuronal survival. For this approach we need support from Biovista for discovery and therapy development work. Positive hits will be then tested on mouse cell cultures by our collaborator at IRCCS Besta in Milan. 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 |
