40武内 敏秀37Toshihide TAKEUCHI植村 知博38Tomohiro UEMURAエクソソームを介した細胞非自律的プロテオスターシス維持機構の解明と神経変性疾患治療への展開（2017採択）Comprehensive understanding of exosome-mediated regulation of proteostasis toward development of molecular therapy for neurodegenerative diseases (Project 2017)超解像ライブイメージングによる植物の病原菌感染応答の可視化システムの開発（2018採択）Establishment of visualization system for immune-response of plant against pathogen by Super-resolution live imaging(Project 2018)多くの神経変性疾患は，タンパク質の凝集・蓄積が原因となって発症する．以前，著者らは分子シャペロンのエクソソーム分泌・伝播を介した新しい生体内防御機構の存在を明らかにし，その活性化による細胞非自律的な神経変性抑制効果を報告した．そこで本研究では，エクソソームを介した生体内防御機構に着目し，その分子機序解明と神経変性疾患における変容解析を行った．その結果，シャペロン分泌を制御する細胞内因子を同定した．また，神経変性疾患で変動するエクソソーム分子を同定した．以上から，エクソソームを介した生体防御機構の一端が解明されるとともに，神経変性疾患の診断バイオマーカー候補分子が得られた．Protein misfolding and aggregation are associated with the onset and progression of many neurodegenerative diseases. Previously we reported that secretion and transmission of molecular chaperones via exosomes, one of the extracellular vesicles, suppress neurodegeneration in a non-cell autonomous manner, contributing to maintenance of protein homeostasis at the organismal level. To elucidate the molecular mechanisms, here we performed comprehensive analysis of exosomal contents using the cellular and animal models of the polyglu-tamine diseases, one of the neurodegenerative diseases. We found that a cellular factor is responsible for se-cretion of molecular chaperones via exosomes. We also found that several exosomal proteins are upregulated or downregulated in the disease models, some of which are confirmed with the samples from the human pa-tients. Our data provide not only insight into the mechanism of exosome-mediated secretion of molecular chaperones but also a promising platform for the development of exosome-based biomarkers for the neurode-generative diseases.トランンスゴルジ網（TGN）は，ゴルジ体のトランス槽の外側に存在する網目状の構造体で，ゴルジ体を通過したタンパク質が機能すべき場所に正しく輸送されるための選別を行うオルガネラである．申請者は超解像ライブイメージングにより，植物にはゴルジ体に隣接するGA-TGN（Golgi-associated TGN）とゴルジ体とは独立して機能するGI-TGN（Golgi-released independent TGN）が存在することを示してきた．しかしながら，GI-TGNがどのような役割を果たすかについては未解明であった．本研究では，GI-TGNが分泌経路で機能し，植物がうどんこ病菌に感染するとGI-TGNを増加させることによって抗菌物質等を積極的に分泌することでうどんこ菌に対する抵抗性を発揮していることを発見した．また，GI-TGNは，GA-TGNの分泌輸送ゾーンから形成されることを明らかにした．The trans-Golgi network (TGN) is an important organelle that acts as a sorting station in the post-Golgi trans-port pathways of plant cells. The TGN also functions as the early endosome, which is the first compartment to receive endocytosed proteins. We have already reported that plant cells possess two types of TGNs. The Gol-gi-associated (GA) TGN is located on the trans-side of the Golgi apparatus, while the Golgi-released inde-pendent (GI) TGN is a mobile and independent organelle that is located away from the Golgi apparatus. However, the physiological roles of GI-TGN remains unknown. In this study, we found that the GI-TGN acts as transit compartment between the Golgi apparatus and PM. We propose a model in which the GA-TGN ma-
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