Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease.
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.
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.
Natalia
N
Rodriguez-Muela
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Nadia K
NK
Litterman
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Erika M
EM
Norabuena
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Jesse L
JL
Mull
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Maria José
MJ
Galazo
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Chicheng
C
Sun
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Shi-Yan
SY
Ng
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Nina R
NR
Makhortova
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Andrew
A
White
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Maureen M
MM
Lynes
Department of Pediatrics, Columbia University, New York, NY 10032, USA.
Wendy K
WK
Chung
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
Lance S
LS
Davidow
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.
Jeffrey D
JD
Macklis
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.
Lee L
LL
Rubin
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000378:metabolism; D009468:Neuromuscular Diseases / Q000378:metabolism*; D055532:SMN Complex Proteins / Q000378:metabolism*; D059010:Single-Cell Analysis / Q000379:methods; D013116:Spinal Cord / Q000378:metabolism
D055532:SMN Complex Proteins
amyotrophic lateral sclerosis; cell death; cell heterogeneity; protein degradation; single cell analysis; spinal muscular atrophy; survival of motor neuron; therapeutics