Ng SY, Soh BS, Rodriguez-Muela N, Hendrickson DG, Price F, Rinn JL, Rubin LL. 2015. Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy. Cell stem cell. 17(5):569-84. Pubmed: 26321202 DOI:S1934-5909(15)00358-6


Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene. Because this gene is expressed ubiquitously, 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 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 the 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 to the study of disease-prone human cells in heterogeneous cultures.
Copyright © 2015 Elsevier Inc. All rights reserved.

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Lee Rubin investigates the key molecular mediators of different neurodegenerative diseases, with the ultimate goal of finding effective preclinical therapeutic candidates.

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