Genetic circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy

Significance Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is a devastating neurodegenerative disease caused by reduced levels of Survival Motor Neuron (SMN) gene activity. Despite well-characterized aspects of the involvement of SMN in small nuclear ribonucleoprotein biogenesis, the gene circuitry affecting SMN activity remains obscure. Here, we use Drosophila as a model system to integrate results from large-scale genetic and proteomic studies and bioinformatic analyses to define a unique SMN interactome to provide a basis for a better understanding of SMA. Such efforts not only help dissect Smn biology but also may point to potential clinically relevant targets. The clinical severity of the neurodegenerative disorder spinal muscular atrophy (SMA) is dependent on the levels of functional Survival Motor Neuron (SMN) protein. Consequently, current strategies for developing treatments for SMA generally focus on augmenting SMN levels. To identify additional potential therapeutic avenues and achieve a greater understanding of SMN, we applied in vivo, in vitro, and in silico approaches to identify genetic and biochemical interactors of the Drosophila SMN homolog. We identified more than 300 candidate genes that alter an Smn-dependent phenotype in vivo. Integrating the results from our genetic screens, large-scale protein interaction studies, and bioinformatic analysis, we define a unique interactome for SMN that provides a knowledge base for a better understanding of SMA.

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