Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy.
Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy.
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DOI：
10.1016/j.stem.2015.08.003
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发表时间：
2015-11-05
期刊：
影响因子：
23.9
通讯作者：
Rubin LL
中科院分区：
文献类型：
--
作者：
Ng SY;Soh BS;Rodriguez-Muela N;Hendrickson DG;Price F;Rinn JL;Rubin LL
Spinal Muscular Atrophy (SMA) is caused by mutations in the SMN1 gene. Because this gene is ubiquitously expressed, it remains poorly understood why motor neurons (MNs) are one of the most affected cell types. To address this question, we carried out RNA-sequencing studies using fixed, antibody-labeled and purified MNs produced from control and SMA patient-derived induced pluripotent stem cells (iPSCs). We found SMA-specific changes in MNs, including hyper-activation of the endoplasmic reticulum (ER) stress pathway. Functional studies demonstrated that inhibition of ER stress improves MN survival in vitro even in MNs expressing low SMN. In SMA mice, systemic delivery of an ER stress inhibitor that crosses the blood-brain-barrier led to preservation of spinal cord MNs. Therefore, our study implies that selective activation of ER stress underlies MN death in SMA. Moreover, the approach we have taken would be broadly applicable for studying disease-prone human cells in heterogeneous cultures.
