title: Systematic analysis of fly models with multiple drivers reveals different effects of ataxin-1 and huntingtin in neuron subtype-specific expression.
abstract: The fruit fly, Drosophila melanogaster, is a commonly used model organism for neurodegenerative diseases. Its major advantages include a short lifespan and its susceptibility to manipulation using sophisticated genetic techniques. Here, we report the systematic comparison of fly models of two polyglutamine (polyQ) diseases. We induced expression of the normal and mutant forms of full-length Ataxin-1 and Huntingtin exon 1 in cholinergic, dopaminergic, and motor neurons, and glial cells using cell type-specific drivers. We systematically analyzed their effects based on multiple phenotypes: eclosion rate, lifespan, motor performance, and circadian rhythms of spontaneous activity. This systematic assay system enabled us to quantitatively evaluate and compare the functional disabilities of different genotypes. The results suggest different effects of Ataxin-1 and Huntingtin on specific types of neural cells during development and in adulthood. In addition, we confirmed the therapeutic effects of LiCl and butyrate using representative models. These results support the usefulness of this assay system for screening candidate chemical compounds that modify the pathologies of polyQ diseases.
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integrative Research, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Shiraishi
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integrative Research, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Biomolecular Science, Faculty of Science, Toho University, Miyama, Funabashi, Chiba, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Sone
authors.affiliation: Department of Neuropathology, Medical Research Institute and Center for Brain Integrative Research, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okazawa
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D000873:Anthracenes / Q000494:pharmacology; D000067696:Ataxin-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001522:Behavior, Animal; D002087:Butyrates / Q000494:pharmacology; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D000071058:Huntingtin Protein; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D018021:Lithium Chloride / Q000494:pharmacology; D008136:Longevity / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023421:Models, Animal; D009043:Motor Activity / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology
chemical_list: D000873:Anthracenes; D000067696:Ataxin-1; D002087:Butyrates; D029721:Drosophila Proteins; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D018021:Lithium Chloride