| First Author | Gallardo G | Year | 2014 |
| Journal | Nat Neurosci | Volume | 17 |
| Issue | 12 | Pages | 1710-9 |
| PubMed ID | 25344630 | Mgi Jnum | J:219419 |
| Mgi Id | MGI:5620815 | Doi | 10.1038/nn.3853 |
| Citation | Gallardo G, et al. (2014) An alpha2-Na/K ATPase/alpha-adducin complex in astrocytes triggers non-cell autonomous neurodegeneration. Nat Neurosci 17(12):1710-9 |
| abstractText | 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 alpha2-Na/K ATPase and alpha-adducin was enriched in astrocytes expressing mutant superoxide dismutase 1 (SOD1), which causes familial amyotrophic lateral sclerosis (ALS). Knockdown of alpha2-Na/K ATPase or alpha-adducin in mutant SOD1 astrocytes protected motor neurons from degeneration, including in mutant SOD1 mice in vivo. Heterozygous disruption of the alpha2-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, alpha2-Na/K ATPase and alpha-adducin were upregulated in spinal cord of sporadic and familial ALS patients. Collectively, our findings define chronic activation of the alpha2-Na/K ATPase/alpha-adducin complex as a critical glial cell-intrinsic mechanism of non-cell autonomous neurodegeneration, with implications for potential therapies for neurodegenerative diseases. |
