An ?2-Na/K ATPase/?-adducin complex in astrocytes triggers non-cell autonomous neurodegeneration.

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 ?2-Na/K ATPase and ?-adducin was enriched in astrocytes expressing mutant superoxide dismutase 1 (SOD1), which causes familial amyotrophic lateral sclerosis (ALS). Knockdown of ?2-Na/K ATPase or ?-adducin in mutant SOD1 astrocytes protected motor neurons from degeneration, including in mutant SOD1 mice in vivo. Heterozygous disruption of the ?2-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, ?2-Na/K ATPase and ?-adducin were upregulated in spinal cord of sporadic and familial ALS patients. Collectively, our findings define chronic activation of the ?2-Na/K ATPase/?-adducin complex as a critical glial cell-intrinsic mechanism of non-cell autonomous neurodegeneration, with implications for potential therapies for neurodegenerative diseases.

SUBMITTER: Gallardo G 

PROVIDER: S-EPMC4703324 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature