論文 - 詳細
| RRC ID | 54543 |
|---|---|
| 著者 | Ihara R, Matsukawa K, Nagata Y, Kunugi H, Tsuji S, Chihara T, Kuranaga E, Miura M, Wakabayashi T, Hashimoto T, Iwatsubo T. |
| タイトル | RNA binding mediates neurotoxicity in the transgenic Drosophila model of TDP-43 proteinopathy. |
| ジャーナル | Hum Mol Genet |
| Abstract |
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss of motor neurons. The discovery of mutations in the gene encoding an RNA-binding protein, TAR DNA-binding protein of 43 kD (TDP-43), in familial ALS, strongly implicated abnormalities in RNA processing in the pathogenesis of ALS, although the mechanisms whereby TDP-43 leads to neurodegeneration remain elusive. To clarify the mechanism of degeneration caused by TDP-43, we generated transgenic Drosophila melanogaster expressing a series of systematically modified human TDP-43 genes in the retinal photoreceptor neurons. Overexpression of wild-type TDP-43 resulted in vacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated by mutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS). Remarkably, these degenerative phenotypes were completely normalized by addition of a mutation or deletion of the RNA recognition motif that abolishes the RNA binding ability of TDP-43. Altogether, our results suggest that RNA binding is key to the neurodegeneration caused by overexpression of TDP-43, and that abnormalities in RNA processing may be crucial to the pathogenesis of TDP-43 proteinopathy. |
| 巻・号 | 22(22) |
| ページ | 4474-84 |
| 公開日 | 2013-11-15 |
| DOI | 10.1093/hmg/ddt296 |
| PII | ddt296 |
| PMID | 23804749 |
| MeSH | Amyotrophic Lateral Sclerosis / genetics Amyotrophic Lateral Sclerosis / metabolism Amyotrophic Lateral Sclerosis / pathology Animals Animals, Genetically Modified Binding Sites Cytosol / metabolism DNA-Binding Proteins / chemistry DNA-Binding Proteins / genetics* DNA-Binding Proteins / metabolism* Disease Models, Animal Drosophila melanogaster / genetics* Drosophila melanogaster / metabolism Humans Nerve Degeneration Phenotype Photoreceptor Cells, Invertebrate / metabolism Photoreceptor Cells, Invertebrate / pathology RNA / metabolism* RNA-Binding Proteins / genetics RNA-Binding Proteins / metabolism Retinal Degeneration / genetics Retinal Degeneration / metabolism Retinal Degeneration / pathology TDP-43 Proteinopathies / genetics TDP-43 Proteinopathies / metabolism TDP-43 Proteinopathies / pathology* |
| IF | 4.544 |
| 引用数 | 39 |
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
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