シンポジウム（Symposium）

Symposium Neuroscience study based on brain bank networking in Japan for the cure of intractable neuropsychiatric disorders シンポジウムオールジャパンブレインバンクネットワーク構築に基づく難治性精神・神経疾患根治療法開発

7月25日（木）15:00～15:30　第2会場（朱鷺メッセ　2F　メインホールA） 1S02a-1 オールジャパンブレンバンクを基盤とする神経変性疾患の病態解明と治療開発 Hitoshi Okazawa（岡澤均）東京医歯大脳統合機能研究セ Neurodegenerative diseases such as Huntington's disease (HD), spinocerebellar ataxia (SCA) and Alzheimer's disease (AD) are defined pathologically as progressive neuronal death with intracellular and/or extracellular protein aggregation. Various molecular events are implicated following and/or in parallel with protein aggregation, while their whole scheme and relative pathological significances remain obscure. We have employed comprehensive analyses such as proteome, phosphoproteome, transcriptome, and interactome to elucidate common and specific pathologies through comparison of such omics data from samples of multiple neurodegenerative diseases including those delivered from the all Japan Brain Bank Network. Comprehensive proteome analyses of HD and SCA revealed that HMGB1/2 were commonly decreased in the nucleus of affected neurons in both diseases by sequestration of protein aggregates or protein degradation following interaction with disease proteins. Genetic complementation of HMGB1 in fly HD and SCA models rescued the rough eye phenotype, and recovered the motor dysfunction and lifespan shortening in mouse SCA model. Moreover, intrathecal administration of AAV-HMGB1 successfully recovered such phenotypes of mouse SCA model. On the other hand, our comprehensive phosphoproteome analysis identified early molecular signature before amyloid aggregation shared by four Alzheimer's disease (AD) mouse models that lasted in postmortem human AD brains. One of the representative molecules was MARCKS, a submembrane molecule regulating the post-synapse structure through actin network, and HMGB1 activates signals to phosphorylate MARCKS through TLR4. We developed anti-HMGB1 antibody therapy to interrupt the pathological signaling and successfully recovered spatial memory of AD model mice. All these data indicate that HMGB1 is a critical good and evil factor contributing to neurodegeneration from inside and outside of neurons. In conclusion, our research history clearly indicates the importance of the all Japan Brain Bank Network for promoting R&D of neurodegenerative diseases.		7月25日（木）15:30～16:00　第2会場（朱鷺メッセ　2F　メインホールA） 1S02a-2 FTLDモデルにおけるTDP-43とDISC1の共凝集による樹状突起での局所翻訳異常と精神障害の発現 Ryo Endo（遠藤良）¹，Noriko Takashima（高嶋紀子）¹，Yoko Nekooki-Machida（猫沖-町田陽子）¹，Yusuke Komi（小見悠介）¹，Kelvin Kai-Wan Hui（Hui Kelvin Kai-Wan）¹，Masaki Takao（高尾昌樹）^2,3，Hiroyasu Akatsu（赤津裕康）^5,6，Shigeo Murayama（村山繁雄）²，Akira Sawa（澤明）⁴，Motomasa Tanaka（田中元雅）¹ ¹理研CBS タンパク質構造疾患 ²東京都健康長寿医療センター ³埼玉医科大学国際医療センター ⁴Johns Hopkins Univ. Sch. of Medicine, USA ⁵福祉村病院長寿医学研究所 ⁶名古屋市立大大学院　医学研究科 Neurodegenerative disorders involving protein misfolding and aggregation are often associated with not only motor deficits but also psychiatric symptoms. In particular, patients of frontotemporal lobar degeneration (FTLD), characterized by atrophy in the frontal and temporal lobes of cerebral cortex, display mental dysfunction in multiple behavioral dimensions. In FTLD brain, TAR DNA-binding protein 43 (TDP-43) is a major component of ubiquitin-positive hyper-phosphorylated inclusions, suggesting that its aggregation is implicated in FTLD pathogenesis. However, it remains largely unclear how TDP-43 aggregation mediates the mental disorders associated with FTLD. In this study, we found novel cytosolic protein aggregates in FTLD brains composed of TDP-43 and DISC1, a biological mediator of mental conditions. At the mechanistic levels, the TDP-43 and DISC1 co-aggregates disrupted activity-dependent dendritic local translation via impairment in translation initiation, resulting in reduced synaptic protein expression. FTLD model mice with DISC1/TDP-43 co-aggregates in frontal cortex showed hyperactivity and social interaction deficits. Remarkably, these phenotypes were rescued by exogenous DISC1 expression to supplement endogenous functional DISC1 that is lost due to its sequestration into TDP-43 aggregates. These results reveal a novel role of the aggregate-prone TDP-43-DISC1 protein complex in regulating local translation, which affects aberrant behaviors relevant to multiple psychiatric dimensions.

7月25日（木）16:00～16:30　第2会場（朱鷺メッセ　2F　メインホールA） 1S02a-3 iPS細胞を用いた希少神経難病の研究 Haruhisa Inoue（井上治久）^1,2,3 ¹京都大iPS細胞研 ²理化学研究所バイオリソース研究センター ³理化学研究所革新知能統合研究センター A rare disease has a prevalence of less than 5 per 10,000, and there are an estimated 5,000-8,000 rare diseases, many of which have neurological manifestations. Although the number of patients with rare diseases is small, learning more about rare diseases could lead to new treatments for common neurological disorders with more complex aetiology. For example, mutations in the same gene as Gaucher disease, a rare inherited lysosomal storage disorder, are a common risk factor predisposing individuals to Parkinson's disease (Lancet Neurol, 2011). The iPSC technology was established a decade or so ago, and enormous progress in stem cell medicine has since been made. Human iPSC-derived neuronal cells, which had previously been inaccessible, now show the exciting promise of multiple applications. Various disease pathomechanisms have been revealed, and new drugs originating from iPSC screens are in the pipeline. In conjunction with that, recent advances in new technologies are providing opportunities to elevate iPSC-based platforms ever higher in the challenge of the disease modeling and drug discovery. Since this characteristic feature presents extraordinary opportunities between iPSCs and rare neurological diseases, the cutting-edge tools, namely, rare disease iPSCs, may provide crucial insights ranging from rare to common neurological diseases. In this presentation, I'd like to talk about our recent efforts and discuss various perspectives of rare disease studies using iPSCs.