title: An α2-Na/K ATPase/α-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 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.
authors.affiliation: 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.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Gallardo
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Barowski
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.affiliation: 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.
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Janice
authors.initials: J
authors.lastname: Robertson
authors.affiliation: Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hanno
authors.initials: H
authors.lastname: Steen
authors.affiliation: 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.
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis*; D000099291:Adducins
chemical_list: D003598:Cytoskeletal Proteins; D000254:Sodium-Potassium-Exchanging ATPase; C581701:Add1 protein, mouse; D000099291:Adducins