並列タイトル等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
一般注記type:Thesis
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.
連携機関・データベース国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）