Cell Reports
Volume 18, Issue 6, 7 February 2017, Pages 1484-1498
Journal home page for Cell Reports

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

https://doi.org/10.1016/j.celrep.2017.01.035Get rights and content
Under a Creative Commons license
open access

Highlights

  • MN cultures from SMA or ALS patients or controls contain cells with different SMN levels

  • In these cultures, high SMN MNs survive better than MNs harboring low SMN levels

  • An Nedd8-activating enzyme inhibitor increases SMN and survival of ALS and SMA MNs

  • The effect of drugs that correct SMN2 splicing is limited to SMA and not ALS

Summary

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.

Keywords

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

Cited by (0)

5

Co-first author

6

Lead Contact