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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.

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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.
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
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.
Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
Tanz Centre for Research in Neurodegenerative Diseases and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.


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.

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