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Cell Rep. 2017 Feb 7;18(6):1484-1498. doi: 10.1016/j.celrep.2017.01.035.

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

Author information

1
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: natalia_rodriguezmuela@harvard.edu.
2
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
3
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
4
Department of Pediatrics, Columbia University, New York, NY 10032, USA.
5
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
6
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: lee_rubin@harvard.edu.

Abstract

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:

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

PMID:
28178525
PMCID:
PMC5463539
DOI:
10.1016/j.celrep.2017.01.035
[Indexed for MEDLINE]
Free PMC Article

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