Spinal muscular atrophy (SMA), the most common genetic cause of infant mortality in the US, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene. Although the underlying genetic mutation is known, the causes of selective motor neuron vulnerability in SMA are not well understood. A team of researchers led by Lee Rubin at the Harvard Stem Cell Institute in Cambridge, MA, performed RNA sequencing on purified motor neurons derived from induced pluripotent stem cells (iPSCs) from SMA patients and healthy controls. As reported in the Aug 27 of Cell Stem Cell online, reduced SMN expression led to hyperactivation of the ER stress response. Motor neuron survival was ameliorated by administering ER stress inhibitors to a mouse model of SMA. This study identifies ER stress as a common pathway implicated in selective motor neuron death in SMA and ALS (see Jan 2015 news), and suggests that drugs targeting the ER stress pathway could potentially benefit both disease groups.
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Ng SY, Soh BS, Rodriguez-Muela N, Hendrickson DG, Price F, Rinn JL, Rubin LL. Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy. Cell Stem Cell. 2015 Aug 27 pii: S1934-5909(15)00358-6. [Pubmed]