title: Ku70 alleviates neurodegeneration in Drosophila models of Huntington's disease.
abstract: DNA damage accumulates in genome DNA during the long life of neurons, thus DNA damage repair is indispensable to keep normal functions of neurons. We previously reported that Ku70, a critical molecule for DNA double strand break (DSB) repair, is involved in the pathology of Huntington's disease (HD). Mutant huntingtin (Htt) impaired Ku70 function via direct interaction, and Ku70 supplementation recovered phenotypes of a mouse HD model. In this study, we generate multiple Drosophila HD models that express mutant huntingtin (Htt) in eye or motor neuron by different drivers and show various phenotypes. In such fly models, Ku70 co-expression recovers lifespan, locomotive activity and eye degeneration. In contrast, Ku70 reduction by heterozygous null mutation or siRNA-mediated knock down accelerates lifespan shortening and locomotion disability. These results collectively support that Ku70 is a critical mediator of the HD pathology and a candidate therapeutic target in HD.
authors.affiliation: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tamura
authors.forename: Masaki
authors.initials: M
authors.lastname: Sone
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tagawa
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D000072200:Ku Autoantigen; D008124:Locomotion / Q000235:genetics / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen
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