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

• Published in: Cell stem cell Vol. 17; no. 5; pp. 569 - 584
• Main Authors: Ng, Shi-Yan, Soh, Boon Seng, Rodriguez-Muela, Natalia, Hendrickson, David G., Price, Feodor, Rinn, John L., Rubin, Lee L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.11.2015
• Subjects: Animals; Cell Death; Cell Differentiation; Cells, Cultured; Endoplasmic Reticulum Stress; Humans; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Medicin och hälsovetenskap; Mice; Mice, Inbred Strains; Mice, Transgenic; Motor Neurons - metabolism; Motor Neurons - pathology; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; RNA - genetics; Sequence Analysis, RNA
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2015.08.003

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. [Display omitted] •Fixed and antibody-labeled motor neurons (MNs) are purified efficiently for RNA-seq•Analysis of purified MNs, not mixed cultures, reveals elevated ER stress in SMA•Abnormal splicing of DNAJC10 in SMA MNs is responsible for increased ER stress•Pharmacological and genetic intervention of the ER stress pathway prevents SMA MN death Loss of the protein SMN causes spinal muscular atrophy, but it is unclear why deficiency in the ubiquitously expressed protein primarily affects motor neurons. In this study, Ng et al. show that a hyperactive ER stress pathway in SMA motor neurons could explain this selective neuronal vulnerability.