title: Tau promotes neurodegeneration via DRP1 mislocalization in vivo.
abstract: Mitochondrial abnormalities have been documented in Alzheimer's disease and related neurodegenerative disorders, but the causal relationship between mitochondrial changes and neurodegeneration, and the specific mechanisms promoting mitochondrial dysfunction, are unclear. Here, we find that expression of human tau results in elongation of mitochondria in both Drosophila and mouse neurons. Elongation is accompanied by mitochondrial dysfunction and cell cycle-mediated cell death, which can be rescued in vivo by genetically restoring the proper balance of mitochondrial fission and fusion. We have previously demonstrated that stabilization of actin by tau is critical for neurotoxicity of the protein. Here, we demonstrate a conserved role for actin and myosin in regulating mitochondrial fission and show that excess actin stabilization inhibits association of the fission protein DRP1 with mitochondria, leading to mitochondrial elongation and subsequent neurotoxicity. Our results thus identify actin-mediated disruption of mitochondrial dynamics as a direct mechanism of tau toxicity in neurons in vivo.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: DuBoff
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
authors.forename: Mel B
authors.initials: MB
authors.lastname: Feany
mesh_terms: D025181:ATP Synthetase Complexes / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018260:Gelsolin / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009218:Myosins / Q000378:metabolism; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism*; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D034622:RNA Interference / Q000502:physiology; D024801:Tauopathies / Q000150:complications* / Q000235:genetics / Q000473:pathology; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D018260:Gelsolin; C054369:MAPT protein, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D050994:Voltage-Dependent Anion Channels; C494761:porin protein, Drosophila; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D025181:ATP Synthetase Complexes; C504426:DRP1 protein, Drosophila; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D009218:Myosins; C110768:DNM1L protein, human; D034281:Dynamins