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


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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Posted on December 27, 2014
Posted in: HPAN, Neurodegeneration, Publications Authors: ,