Survival motor Neuron protein regulates apoptosis in anin vitro model of Spinal muscular atrophy

Progressive spinal muscular atrophy (SMA), the most prevalent hereditary lower motor neuron disease, is caused by mutations in the telomeric copy of the survival of motor neuron(SMN1) gene. Unlike other cells, lower motor neurons cannot tolerate low levels of smn protein. However, it is unclear as to the nature of the cell death involved. There is evidence that lower motor neurons undergo apoptosis in SMA, leading to muscle weakness and wasting. This study investigated whetherSMN1 regulation in a motor neuron model affected indices of apoptotic cell death. Decreased smn expression in neuroblas-toma hybrid (NSC-34) cell lines by small interfering RNA (siRNA) was demonstrated at the mRNA and protein level. Smn-depleted cells showed elevated caspase-3 activity, decreased cell viability and increased percentage of TUNEL positive cells. Conversely, NSC-34 cell smn overexpression by adenoviral gene transfer decreased staurosporine-induced caspase-3 elevation and mitigated induced cell toxicity as assessed by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. However, increased smn expression by itself did not increase cell viability. These data suggest not only that decreased smn levels increase apoptosis in anin vitro model of SMA, but also that increased smn can protect against neural injury.