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Cell Stem Cell. 2015 Nov 5;17(5):569-84. doi: 10.1016/j.stem.2015.08.003. Epub 2015 Aug 27.

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

Author information

1
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
2
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.
3
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.
4
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.
5
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.

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.

PMID:
26321202
PMCID:
PMC4839185
DOI:
10.1016/j.stem.2015.08.003
[Indexed for MEDLINE]
Free PMC Article

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