nusinersen and Inflammation

The deficiency of survival motor neuron (SMN) protein can result in the onset of spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by a progressive loss of motor neurons and skeletal muscle atrophy. The mechanism underlying SMA pathology remains unclear. Here, we demonstrate that SMN protein regulates oxidative stress and inflammatory response in microglia. Antisense oligonucleotide, which increases SMN protein expression (SMN-ASO), attenuated SMA model mice phenotypes and suppressed the activation of microglia in the spinal cord. The expression of oxidative stress marker in microglia was decreased by SMN-ASO injection in SMA model mice. Increased reactive oxygen species production and subsequent antioxidative stress reaction was observed in SMN protein-depleted RAW264.7. Furthermore, nuclear factor kappa B (NFκB) and c-Jun amino terminal kinase (JNK) signaling, which mainly mediate the inflammatory response, are activated in SMN protein-depleted RAW264.7. Tumor necrosis factor-α (TNF-α) production is also increased in SMN protein-depleted RAW264.7. These findings suggest that SMN protein regulates oxidative stress and inflammatory response in microglia, supporting current claims that microglia can be an effective target for SMA therapy.

Topics: Animals; Disease Models, Animal; Gene Expression; Inflammation; MAP Kinase Signaling System; Mice; Mice, Transgenic; Microglia; Molecular Targeted Therapy; Muscular Atrophy, Spinal; NF-kappa B; Oligonucleotides; Oligonucleotides, Antisense; Oxidative Stress; RAW 264.7 Cells; Spinal Cord; Survival of Motor Neuron 1 Protein; Tumor Necrosis Factor-alpha