RRC ID 46765
著者 Matsukawa K, Hashimoto T, Matsumoto T, Ihara R, Chihara T, Miura M, Wakabayashi T, Iwatsubo T.
タイトル 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.
ジャーナル J Biol Chem
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.
巻・号 291(45)
ページ 23464-23476
公開日 2016-11-4
DOI 10.1074/jbc.M116.729152
PII S0021-9258(20)35626-X
PMID 27634045
PMC PMC5095402
MeSH Amyotrophic Lateral Sclerosis / complications Amyotrophic Lateral Sclerosis / genetics* Amyotrophic Lateral Sclerosis / metabolism Amyotrophic Lateral Sclerosis / pathology Animals Cytoplasm / genetics Cytoplasm / metabolism Cytoplasm / pathology DNA-Binding Proteins / analysis DNA-Binding Proteins / genetics* DNA-Binding Proteins / metabolism Drosophila melanogaster / genetics Drosophila melanogaster / physiology HEK293 Cells Humans Mutation Profilins / analysis Profilins / genetics* Retina / metabolism Retina / pathology* Retinal Degeneration / complications Retinal Degeneration / genetics* Retinal Degeneration / metabolism Retinal Degeneration / pathology Up-Regulation
IF 4.238
引用数 9
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ショウジョウバエ 9553R-3