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Cell Stem Cell DOI:10.1016/j.stem.2015.08.003

Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy.

Publication TypeJournal Article
Year of Publication2015
AuthorsNg, S-Y, Soh, BSeng, Rodriguez-Muela, N, Hendrickson, DG, Price, F, Rinn, JL, Rubin, LL
JournalCell Stem Cell
Date Published2015 Nov 05
KeywordsAnimals, Cell Death, Cell Differentiation, Cells, Cultured, Endoplasmic Reticulum Stress, Humans, Induced Pluripotent Stem Cells, Mice, Mice, Inbred Strains, Mice, Transgenic, Motor Neurons, Muscular Atrophy, Spinal, RNA, Sequence Analysis, RNA

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.


Alternate JournalCell Stem Cell
PubMed ID26321202
PubMed Central IDPMC4839185
Grant ListP01 NS066888 / NS / NINDS NIH HHS / United States
1P01NS066888 / NS / NINDS NIH HHS / United States