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Nat Neurosci. 2014 Dec;17(12):1710-9. doi: 10.1038/nn.3853. Epub 2014 Oct 26.

An α2-Na/K ATPase/α-adducin complex in astrocytes triggers non-cell autonomous neurodegeneration.

Author information

1
1] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
3
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
4
1] Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA. [2] Department of Molecular and Cellular Biology, Northwestern Feinberg School of Medicine, Chicago, Illinois, USA.
5
Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
6
Tanz Centre for Research in Neurodegenerative Diseases and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
7
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Perturbations of astrocytes trigger neurodegeneration in several diseases, but the glial cell-intrinsic mechanisms that induce neurodegeneration remain poorly understood. We found that a protein complex of α2-Na/K ATPase and α-adducin was enriched in astrocytes expressing mutant superoxide dismutase 1 (SOD1), which causes familial amyotrophic lateral sclerosis (ALS). Knockdown of α2-Na/K ATPase or α-adducin in mutant SOD1 astrocytes protected motor neurons from degeneration, including in mutant SOD1 mice in vivo. Heterozygous disruption of the α2-Na/K ATPase gene suppressed degeneration in vivo and increased the lifespan of mutant SOD1 mice. The pharmacological agent digoxin, which inhibits Na/K ATPase activity, protected motor neurons from mutant SOD1 astrocyte-induced degeneration. Notably, α2-Na/K ATPase and α-adducin were upregulated in spinal cord of sporadic and familial ALS patients. Collectively, our findings define chronic activation of the α2-Na/K ATPase/α-adducin complex as a critical glial cell-intrinsic mechanism of non-cell autonomous neurodegeneration, with implications for potential therapies for neurodegenerative diseases.

PMID:
25344630
PMCID:
PMC4703324
DOI:
10.1038/nn.3853
[Indexed for MEDLINE]
Free PMC Article

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