SMN (Survival Motor Neuron) deﬁciency is the predominant cause of spinal muscular atrophy (SMA), a severe neurodegenerative disorder that can lead to progressive paralysis and death. Although SMN is required in every cell for proper RNA metabolism, the reason why its loss is especially critical in the motor system is still unclear. The SMA disease models developed in flies and worms, recapitulate the neuromuscular defects of SMA patients leading to identify several modiﬁers that can ameliorate the deﬁcits induced by SMN depletion.. Genetic and molecular analyses performed using Drosophila melanogaster and Caenorhabditis elegans as model systems, revealed that WDR79 and TGS1, two proteins which cooperate with SMN in humans, can improve some aspects of the SMN deficiency. WDR79 depletion results in locomotion defects in both Drosophila and C. elegans, similar to those elicited by SMN depletion. Consistent with this observation, we found that SMN overexpression rescues the phenotypic defects caused by WDR79 loss-of-function and most importantly that WDR79 overexpression ameliorates the locomotion defects induced by SMN depletion in both ﬂies and worms. Furthermore, our preliminary data suggest that overexpression of TGS1, whose loss results in a phenotype similar to that elicited by SMN depletion, ameliorates locomotion and post-eclosion defects in flies depleted of SMN. Collectively our results indicate that the WDR79 and TGS1 proteins play evolutionarily conserved functions cooperating with SMN in the nervous system and suggest a potential use to modify SMA pathogenesis. Because so far there are not effective therapies for SMA patients, the identification of new modifiers of the SMN function could suggest new therapeutic strategies aimed at ameliorating the symptoms of the disease.
A Drosophila model of SMA: isolation and characterization of two novel SMN modifiers / Maccallini, Paolo. - (2018 Feb 15).
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