Smn1 is the gene responsible for Spinal Muscular Atrophy (SMA), a devastating disease characterized by progressive degeneration and death of a specific subclass of motor neurons. The lethality associated with loss of function mutations in Smn1 has made the study of its function hard to investigate in any animal model. In C. elegans, two mutants in Smn1/smn-1 are available, which present some limitation for manipulation and no neurodegeneration (Briese et al., HMG, 2009; Sleigh et al., HMG, 2010). To overcome these limits and investigate the role of
smn-1 in the nervous system, we used a neuron-specific RNAi strategy (Esposito et al., Gene, 2007) to silence
smn-1 selectively in the GABAergic motor neurons. These animals, viable and fertile, presented an altered backward movement and an age-dependent degeneration specifically in these motor neurons, detected as disappearance of presynaptic and cytoplasmic fluorescent markers, and as positive reactivity to genetic and chemical cell-death markers (Gallotta et al., HMG 2016). We then determined that homologs of Smn1 modulators identified in other species, such as Plastin3/plst-1, genetically interacts with
smn-1 for neuron survival and that valproic acid, a drug successfully used in SMA mouse models, partially reverts this phenotype. We also demonstrated that genes of the classical apoptosis pathway, and not of the necrotic pathway, are involved in the
smn-1-mediated neuronal death. Remarkably, this phenotype was rescued by the expression of human Smn1, indicating a strong functional conservation between the two genes. To determine the neuron-specific effects of
smn-1 depletion, we silenced it in the touch receptor neurons, revealing cell-specific phenotypes and molecular machineries activated by lack of
smn-1. Finally, by forward and reverse genetics approaches we identified several genes that interact with
smn-1 to either worsen or rescue the degeneration. Some of these genes impair the RNAi pathway (e.g.
rde-1), others are able to prevent the apoptotic death but not the degeneration, while others fully protect neuronal function, integrity and survival (e.g. Y105E8A.8). Some of the neuroprotective genes identified have been tested for suppressing different neurodegenerative models (e.g. axon degeneration or a-syn overexpression) and we found that a subset of them has a general protective role, while others are specific to our SMA model, providing a unique new framework to elucidate the molecular mechanisms that underlie neuron degeneration.