Pharmacological Activation of Autophagy Ameliorates Neuromuscular-Associated Defects and Extends Lifespan in a Caenorhabditis elegans Model of Spinal Muscular Atrophy

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Abstract Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by homozygous deletions or mutations in the SMN1 gene, resulting in reduced levels of the ubiquitously expressed survival motor neuron protein and progressive degeneration of lower motor neurons. Although autophagy dysregulation has been implicated in SMA pathology, the therapeutic benefit of modulating this pathway remains controversial. Here, we screened autophagy modulators in a previously characterized Caenorhabditis elegans SMA model. We identified that pharmacological activation of autophagy, but not inhibition, significantly improved neuromuscular function, as indicated by two independent functional readouts: pharyngeal pumping and locomotor activity assays. These beneficial effects were validated in an independent severe C. elegans SMA mutant allele and were observed in metabolically active and inactive food conditions. Furthermore, autophagy activators significantly extended lifespan of SMA nematodes without affecting controls. Notably, rapamycin and resveratrol increased endogenous SMN-1 protein levels, and improved neuromuscular function was dependent on an intact autophagy pathway. Collectively, our findings support enhancing autophagic activity as a combinatorial treatment strategy for SMA patients.

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