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

Gilbert Gallardo, Jessica Barowski, John Ravits, Teepu Siddique, Jerry B. Lingrel, Janice Robertson, Hanno Steen, Azad Bonni

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish
Pages (from-to)1710-1719
Number of pages10
JournalNature neuroscience
Volume17
Issue number12
DOIs
StatePublished - Jan 1 2014

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    Gallardo, G., Barowski, J., Ravits, J., Siddique, T., Lingrel, J. B., Robertson, J., Steen, H., & Bonni, A. (2014). An α2-Na/K ATPase/α-adducin complex in astrocytes triggers non-cell autonomous neurodegeneration. Nature neuroscience, 17(12), 1710-1719. https://doi.org/10.1038/nn.3853