Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism.
Oligodendrocytes have recently been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). Here we show that, in vitro, mutant superoxide dismutase 1 (SOD1) mouse oligodendrocytes induce WT motor neuron (MN) hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls and patients with sporadic and familial ALS, using two different reprogramming methods. All ALS oligodendrocyte lines induced MN death through conditioned medium (CM) and in coculture. CM-mediated MN death was associated with decreased lactate production and release, whereas toxicity in coculture was lactate-independent, demonstrating that MN survival is mediated not only by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in MN rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, whereas it was ineffective in differentiated oligodendrocytes. In fact, early SOD1 knockdown rescued lactate impairment and cell toxicity in all lines tested, with the exclusion of samples carrying chromosome 9 ORF 72 (C9orf72) repeat expansions. These did not respond to SOD1 knockdown nor did they show lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type, some damage might be irreversible. In addition, we demonstrate that patients with C9ORF72 represent an independent patient group that might not respond to the same treatment.
The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205; Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, United Kingdom.
Laura
L
Ferraiuolo
The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205.
Kathrin
K
Meyer
Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
Thomas W
TW
Sherwood
Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
Jonathan
J
Vick
The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205; Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210.
Shibi
S
Likhite
The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205; Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210.
Ashley
A
Frakes
The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205.
Carlos J
CJ
Miranda
The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205.
Lyndsey
L
Braun
Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, United Kingdom.
Paul R
PR
Heath
Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
Ricardo
R
Pineda
Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
Christine E
CE
Beattie
Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, United Kingdom.
Pamela J
PJ
Shaw
Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
Candice C
CC
Askwith
Department of Neuroscience, The Ohio State University, Columbus, OH 43210.
Dana
D
McTigue
The Research Institute, Nationwide Children's Hospital, Columbus, OH 43205; Department of Neuroscience, The Ohio State University, Columbus, OH 43210; Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210; Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210 Brian.Kaspar@NationwideChildrens.org.
Brian K
BK
Kaspar
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D000073885:C9orf72 Protein / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication; D016923:Cell Death; D002454:Cell Differentiation; D002470:Cell Survival; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D000072105:Superoxide Dismutase-1 / Q000235:genetics* / Q000378:metabolism
D015415:Biomarkers; D000073885:C9orf72 Protein; D019344:Lactic Acid; D000072105:Superoxide Dismutase-1
C9orf72; SOD1; amyotrophic lateral sclerosis; lactate; oligodendrocytes
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