title: Familial Amyotrophic Lateral Sclerosis-linked Mutations in Profilin 1 Exacerbate TDP-43-induced Degeneration in the Retina of Drosophila melanogaster through an Increase in the Cytoplasmic Localization of TDP-43.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons. Causative genes for familial ALS (fALS), e.g. TARDBP or FUS/TLS, have been found, among which mutations within the profilin 1 (PFN1) gene have recently been identified in ALS18. To elucidate the mechanism whereby PFN1 mutations lead to neuronal death, we generated transgenic Drosophila melanogaster overexpressing human PFN1 in the retinal photoreceptor neurons. Overexpression of wild-type or fALS mutant PFN1 caused no degenerative phenotypes in the retina. Double overexpression of fALS mutant PFN1 and human TDP-43 markedly exacerbated the TDP-43-induced retinal degeneration, i.e. vacuolation and thinning of the retina, whereas co-expression of wild-type PFN1 did not aggravate the degenerative phenotype. Notably, co-expression of TDP-43 with fALS mutant PFN1 increased the cytoplasmic localization of TDP-43, the latter remaining in nuclei upon co-expression with wild-type PFN1, whereas co-expression of TDP-43 lacking the nuclear localization signal with the fALS mutant PFN1 did not aggravate the retinal degeneration. Knockdown of endogenous Drosophila PFN1 did not alter the degenerative phenotypes of the retina in flies overexpressing wild-type TDP-43 These data suggest that ALS-linked PFN1 mutations exacerbate TDP-43-induced neurodegeneration in a gain-of-function manner, possibly by shifting the localization of TDP-43 from nuclei to cytoplasm.
authors.affiliation: From the Departments of Neuropathology, Graduate School of Medicine.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsukawa
authors.affiliation: From the Departments of Neuropathology, Graduate School of Medicine.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: From the Departments of Neuropathology, Graduate School of Medicine.|Neuropathology and Neuroscience, and.
authors.forename: Taisei
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: From the Departments of Neuropathology, Graduate School of Medicine.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Ihara
authors.affiliation: Genetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Chihara
authors.affiliation: Genetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miura
authors.affiliation: From the Departments of Neuropathology, Graduate School of Medicine.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: From the Departments of Neuropathology, Graduate School of Medicine, iwatsubo@m.u-tokyo.ac.jp.|Neuropathology and Neuroscience, and.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D051304:Profilins / Q000032:analysis / Q000235:genetics*; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C495738:PFN1 protein, human; D051304:Profilins; C000598624:TARDBP protein, human
keywords: Drosophila; TAR DNA-binding protein 43 (TDP-43) (TARDBP); amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease); fused in sarcoma (FUS); neurodegeneration; neurodegenerative disease; profilin