Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.
Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Evangelos
E
Kiskinis
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Jackson
J
Sandoe
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Luis A
LA
Williams
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Gabriella L
GL
Boulting
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Rob
R
Moccia
FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02115, USA.
Brian J
BJ
Wainger
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Steve
S
Han
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Theodore
T
Peng
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, Departments of Pathology, Neurology and Neuroscience, Columbia University, Center for Motor Neuron Biology and Disease (MNC), and Columbia Stem Cell Initiative (CSCI), New York, NY 10027, USA.
Sebastian
S
Thams
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Shravani
S
Mikkilineni
FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Cassidy
C
Mellin
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Florian T
FT
Merkle
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Brandi N
BN
Davis-Dusenbery
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Michael
M
Ziller
Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, Departments of Pathology, Neurology and Neuroscience, Columbia University, Center for Motor Neuron Biology and Disease (MNC), and Columbia Stem Cell Initiative (CSCI), New York, NY 10027, USA.
Derek
D
Oakley
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Justin
J
Ichida
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Stefania
S
Di Costanzo
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA.
Nick
N
Atwater
Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Morgan L
ML
Maeder
Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Mathew J
MJ
Goodwin
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
James
J
Nemesh
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Robert E
RE
Handsaker
The New York Stem Cell Foundation Research Institute, New York, NY 10023, USA.
Daniel
D
Paull
The New York Stem Cell Foundation Research Institute, New York, NY 10023, USA.
Scott
S
Noggle
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Steven A
SA
McCarroll
Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
J Keith
JK
Joung
FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Clifford J
CJ
Woolf
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Robert H
RH
Brown
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02138, USA. Electronic address: eggan@mcb.harvard.edu.
Kevin
K
Eggan
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1