Identification of new druggable targets and potential therapeutic compounds for Spinal Muscular Atrophy, using a C.elegans model of neurodegeneration

Spinal muscular atrophy (SMA) is a disease characterized by the progressive degeneration of nerve cells, leading to the atrophy of muscles, paralysis and finally death. Based on age of onset and motor abilities, SMA can be clinically subdivided into three main types: a severe (type I), an intermediate (II), and a milder form (III). Additional forms have been described: type 0 is a prenatal form that is fatal in utero or at few months, while type IV is an adult onset form with mild muscle weakness and normal life expectancy. SMA is one of the most common genetic causes of infant mortality and is caused by disruption of Smn1 gene. The function of Smn1 protein has been extensively studied, but the mechanisms underlying cell death are still elusive and treatment approaches for the disease are still under investigation. The identification of genes interacting with Smn1 can provide new targets for treatments, but this requires a detailed knowledge of Smn1 function. We propose to use a small invertebrate, the nematode worm C. elegans, as a model system to rapidly identify other genes that interact with Smn1 and, possibly, to identify new potential therapeutic targets. C. elegans is a powerful and low cost model useful to study the degenerative process in vivo and to directly assess the effectiveness of new drugs, providing a unique feature to allow visualization of nerve cells in living animals. C. elegans has already been successfully used for the identification of small molecules to correct some of the SMA-related defects. For instance, we already demonstrated in this model that valproic acid, a drug used in clinical trials for SMA patients, partially prevents nerve cell death. In this project, we will use genetic manipulations, drug treatments and phenotypic analysis to identify genetic and chemical modifiers of Smn1 function, strictly focusing on the correction of nerve cell death. Data from the C. elegans settings will be immediately translated in a mouse model to confirm the efficacy of the proposed therapeutic strategy. We expect to gather sufficient data to refine future strategies for restoring Smn1 function in SMA patients, thus preventing neuronal death.