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Studies on suppressive effect of cancer-related genes on pathogenesis of FTLD/ALS by using Drosophila models
http://hdl.handle.net/10212/2542
http://hdl.handle.net/10212/25423b2f2e10-cf8b-492c-a83a-25e0ae42ec38
| 名前 / ファイル | ライセンス | アクション |
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全文 (241.2 MB)
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内容・審査結果の要旨 (281.9 KB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||||
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| 公開日 | 2022-04-20 | |||||||||
| タイトル | ||||||||||
| タイトル | Studies on suppressive effect of cancer-related genes on pathogenesis of FTLD/ALS by using Drosophila models | |||||||||
| 言語 | en | |||||||||
| その他のタイトル | ||||||||||
| その他のタイトル | ショウジョウバエモデルを用いた癌関連遺伝子のFTLD/ALS発症抑制効果に関する研究 | |||||||||
| 言語 | ja | |||||||||
| 作成者 |
山本, 格
× 山本, 格
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| アクセス権 | ||||||||||
| アクセス権 | open access | |||||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Frontotemporal lobar degeneration (FTLD) | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Amyotrophic lateral sclerosis (ALS) | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Drosophila | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Fused in sarcoma (FUS) | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Myelodysplastic syndrome (MDS) | |||||||||
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| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Acute myeloid leukemia (AML) | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Nucleophosmin-human myeloid leukemia factor 1 (NPM-hMLF1) | |||||||||
| 主題 | ||||||||||
| 言語 | en | |||||||||
| 主題Scheme | Other | |||||||||
| 主題 | Hippo pathway | |||||||||
| 内容記述 | ||||||||||
| 内容記述タイプ | Abstract | |||||||||
| 内容記述 | More than 50 mutations in the Fused in sarcoma (FUS) gene have been identified to date in Amyotrophic lateral sclerosis (ALS). Although mutations in the FUS gene have rarely been reported in Frontotemporal lobar degeneration (FTLD), the majority of FTLD-FUS cases have inclusions with wild-type FUS. Therefore, although ALS and FTLD show significant heterogeneity in their clinical symptoms, the overlap in genetics and pathology prompted us to consider ALS and FTLD as a spectrum. In this thesis, I examined the effects of cancer-related genes including the nucleophosmin-human myeloid leukemia factor 1 (NPM-hMLF1) gene and the hpo gene, a Drosophila homologue of the mammalian Ste20-like (MST) gene, on pathogenesis of FTLD/ALS Drosophila models. After summarizing general background of the study in Chapter 1, suppressive effect of NPM-hMLF1 on defects of transgenic flies carrying human FUS (hFUS) gene are described in Chapter 2. Co-expression of NPM-hMLF1 suppressed the rough eye phenotype induced by eye imaginal discs-specific expression of hFUS. In addition, co-expression of NPM-hMLF1 rescued pharate adult lethal phenotype induced by motor neuron-specific expression of hFUS. Surprisingly, the driving of hFUS expression at 28°C rather down-regulated levels of hFUS and Drosophila FUS homolog, cabeza (caz). The down-regulation was mediated by proteasome dependent degradation. Co-expression of NPM-hMLF1 suppressed this down-regulation. Moreover, co-expression of NPM-hMLF1 increased the solubility of hFUS protein that forms aggregates in nucleus. In Chapter 3, suppressive effects of loss-of-function mutations of hpo on defects of caz knockdown flies are described. Loss-of-function mutations of hpo suppressed the rough eye phenotype induced by eye imaginal discs-specific knockdown of caz. Moreover, loss-of-function mutations of hpo suppressed climbing disability and morphological defects of neuromuscular junctions induced by neuron-specific knockdown of caz that mimics human ALS symptoms. Knockdown of caz led to increase of the expression level of hpo, suggesting that caz negatively regulates the hpo gene expression. Loss-of-function mutations of hpo rescued nuclear localization of caz that may be mediated by inhibition of autophagy. Finally, in Chapter 4, conclusion and perspectives are described. | |||||||||
| 言語 | en | |||||||||
| 日付 | ||||||||||
| 日付 | 2019-09-25 | |||||||||
| 日付タイプ | Issued | |||||||||
| 言語 | ||||||||||
| 言語 | eng | |||||||||
| 資源タイプ | ||||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||||
| 資源タイプ | doctoral thesis | |||||||||
| 出版タイプ | ||||||||||
| 出版タイプ | VoR | |||||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||||
| 学位授与番号 | ||||||||||
| 学位授与番号 | 甲第932号 | |||||||||
| 学位名 | ||||||||||
| 言語 | ja | |||||||||
| 学位名 | 博士（学術） | |||||||||
| 学位授与年月日 | ||||||||||
| 学位授与年月日 | 2019-09-25 | |||||||||
| 学位授与機関 | ||||||||||
| 学位授与機関識別子Scheme | kakenhi | |||||||||
| 学位授与機関識別子 | 14303 | |||||||||
| 言語 | ja | |||||||||
| 学位授与機関名 | 京都工芸繊維大学 | |||||||||
