title: Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy.
abstract: 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.
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors: Shi-Yan
authors: SY
authors: Ng
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden.
authors: Boon Seng
authors: BS
authors: Soh
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors: Natalia
authors: N
authors: Rodriguez-Muela
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
authors: David G
authors: DG
authors: Hendrickson
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors: Feodor
authors: F
authors: Price
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
authors: John L
authors: JL
authors: Rinn
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: lee_rubin@harvard.edu.
authors: Lee L
authors: LL
authors: Rubin
mesh_terms: D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000235:genetics*; D017423:Sequence Analysis, RNA
chemical_list: D012313:RNA