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Cell Stem Cell. 2014 Jun 5;14(6):781-95. doi: 10.1016/j.stem.2014.03.004. Epub 2014 Apr 3.

Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.

Author information

1
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.
2
The Howard Hughes Medical Institute, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
3
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.
4
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.
5
FM Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
6
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
7
Molecular Pathology Unit, Center for Computational and Integrative Biology, and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
8
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.
9
The New York Stem Cell Foundation Research Institute, New York, NY 10023, USA.
10
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
11
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.

Abstract

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.

Comment in

PMID:
24704492
PMCID:
PMC4653065
DOI:
10.1016/j.stem.2014.03.004
[Indexed for MEDLINE]
Free PMC Article

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