Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease

Cell Reports

Wendy K. Chung¹  Erika M. Norabuena²  Jeffrey D. Macklis²  Natalia Rodriguez-Muela²  Andrew White²  Lance S. Davidow²  Maureen M. Lynes²  Nadia K. Litterman²  Shi-Yan Ng²  Lee L. Rubin²  Jesse L. Mull²  Chicheng Sun²  Maria José Galazo²  Nina R. Makhortova² 

[1] Department of Pediatrics, Columbia University, New York, NY 10032, USA;Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA;

关键词: spinal muscular atrophy;    amyotrophic lateral sclerosis;    survival of motor neuron;    single cell analysis;    cell heterogeneity;    therapeutics;    protein degradation;    cell death;   

DOI  :  10.1016/j.celrep.2017.01.035

来源: DOAJ

【 摘 要 】

The mechanism underlying selective motor neuron (MN) death remains an essential question in the MN disease field. The MN disease spinal muscular atrophy (SMA) is attributable to reduced levels of the ubiquitous protein SMN. Here, we report that SMN levels are widely variable in MNs within a single genetic background and that this heterogeneity is seen not only in SMA MNs but also in MNs derived from controls and amyotrophic lateral sclerosis (ALS) patients. Furthermore, cells with low SMN are more susceptible to cell death. These findings raise the important clinical implication that some SMN-elevating therapeutics might be effective in MN diseases besides SMA. Supporting this, we found that increasing SMN across all MN populations using an Nedd8-activating enzyme inhibitor promotes survival in both SMA and ALS-derived MNs. Altogether, our work demonstrates that examination of human neurons at the single-cell level can reveal alternative strategies to be explored in the treatment of degenerative diseases.

【 授权许可】

Unknown