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

Abstract

SUMMARY Spinal Muscular Atrophy (SMA) is caused by mutations in the SMN1 gene. Because this gene is ubiquitously expressed, 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 endoplasmic reticulum (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 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 for studying disease-prone human cells in heterogeneous cultures.

A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency

“…Our findings reveal that SMN deficiency induces selective MN death in vitro that is mediated by cell autonomous mechanisms. This is in agreement with previous in vitro and in vivo studies that used stem cell-derived mouse and human MNs (Ebert et al, 2009; Makhortova et al, 2011; Sareen et al, 2012; Ng et al, 2015) as well as selective restoration of SMN in MNs of SMA mice (Gogliotti et al, 2012; Martinez et al, 2012; McGovern et al, 2015) and conditional SMN depletion from MNs of wild type mice (Park et al, 2010; McGovern et al, 2015). Thus, our model system recapitulates a key feature of the human disease and supports the conclusion that SMN reduction has differential effects on the survival of MNs relative to other types of neurons.…”

“…Thus, our model system recapitulates a key feature of the human disease and supports the conclusion that SMN reduction has differential effects on the survival of MNs relative to other types of neurons. While the precise molecular mechanisms remain to be fully elucidated, recent work has implicated selective activation of ER stress in the death pathway of SMA MNs (Ng et al, 2015). …”

SMN - A chaperone for nuclear RNP social occasions?

“…Previously, low levels of SMN have been linked to widespread changes in expression patterns, [121][122][123][124][125][126][127][128] but it is currently an open question as to how these changes might be linked to Cajal bodies. In addition, the mechanism by which these conformational changes in the nucleus affect the rest of the cell and which cellular components and processes are most severely affected has yet to be studied.…”

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

“…We previously showed that, consistent with the clinical features of the disease in SMA patients, spinal motor neurons innervating proximal muscles are preferentially affected and degenerate early in the disease process compared to those that innervate distal muscles and are relatively spared (Mentis et al, 2011). To date, several effector pathways have been implicated in the process of motor neuron death in SMA, which include tau phosphorylation (Miller et al, 2015), ER stress (Ng et al, 2015), and c-Jun N-terminal kinase 3 (JNK3) activation (Genabai et al, 2015) among others. However, the events that trigger degeneration of motor neurons, but not of other spinal neurons in SMA remain poorly defined.…”