公募シンポジウム

公募シンポジウム6【神経細胞の発達異常に対するエピジェネティック変異の寄与と制御】

2021/9/30　14:00～16:00　ZOOM C会場 S6-1 化学物質による小脳発達異常をもたらすエピジェネティックな変化 ^○吉田祥子豊橋技術科学大学 ^○Sachiko Yoshida Toyohashi University of Technology Chemical exposure in utero has potential effects on developmental neurotoxicity (DNT). Multiple chemicals, for example, sodium valproate (VPA), chlorpyrifos (CPF), or lipopolysaccharide (LPS), have been associated with an increased risk of ASD. We have observed that VPA-administrated rat showed the excess development of Purkinje cells and excess folding between the V to VI lobules of cerebellar vermis within two weeks after birth with dose-dependent and administrated-period dependent manner. Cerebellar excess development is maintained in adults, and its alteration is similar to the human early ASD cerebellum. The irregular folding of vermis appeared in butyrate-, LPS- and CPF-administrated rat cerebellum in early weeks. This irregular folding of lobules appeared even in the P5 cerebellum of the VPA-administrated rat. Meanwhile, the expressions of the astrocyte-specific glutamate transporter, GLAST, and GFAP were increased with the decrease of H3K9me expression in the P7 molecular layer. We suggest the epigenetic alteration of developing cerebellum with chemical exposure would induce the early development of astrocytes and GLAST expression, which would prevent pruning of immature Purkinje cells to hyperplasia		2021/9/30　14:00～16:00　ZOOM C会場 S6-2 レット症候群原因因子MeCP2 のmiRNA を介した神経幹細胞分化制御機構 Prenatal chemical exposure induced developmental neurotoxicity due to epigenetic alterations ^○中島欽一九州大学大学院医学研究院 ^○Kinichi Nakashima Graduate School of Medical Sciences, Kyushu University Rett syndrome (RTT) is a severe neurological disorder with impaired brain development caused by mutations in MECP2, yet the underlying mechanism remains elusive. We have previously discovered that MeCP2 facilitates processing of a specific microRNA, miR-199a, by associating with Drosha complex to regulate neuronal functions. Here, we show that the MeCP2/miR-199a axis regulates neural stem/precursor cell (NS/PC) differentiation. We found a shift from neuronal to astrocytic differentiation of MeCP2- and miR-199a-deficient NS/PCs due to the upregulation of a miR-199a target, Smad1, a downstream transcription factor of bone morphogenetic protein (BMP) signaling. Moreover, miR-199a expression and treatment with BMP inhibitors rectified differentiation of RTT patient-derived NS/PCs and development of brain organoids, respectively, suggesting that facilitation of BMP signaling accounts for the impaired RTT brain development. Our study provides new insights into the molecular pathology of RTT and reveals the MeCP2/miR-199a/Smad1 axis as a potential therapeutic target for RTT.

2021/9/30　14:00～16:00　ZOOM C会場 S6-3 中枢神経性疾患治療を目指したエピジェネティクス制御化合物の創製 Discovery of epigenetic inhibitors targeting neurological disorders ^○鈴木孝禎大阪大学産業科学研究所 ^○Takayoshi Suzuki The Institute of Scientific and Industrial Research, Osaka University Epigenetic aberrations are associated with neurological disorders. Therefore, neurological disorders could be treated by controlling epigenetics. To this end, we have studied epigenetic inhibitors focusing on histone modification enzymes, especially histone deacetylases (HDACs) histone lysine demethylases (KDMs). HDAC2 is involved in neurological disorders such as Alzheimer’s disease. Therefore, there is a need of HDAC2-selective inhibitors as anti-dementia agents as well as tools for probing the biological functions of the isoforms. However, it is considerably difficult to identify thermodynamically HDAC1- and HDAC2-selective inhibitors due to high sequence identify (>85%) and sequence similarity (>93%) between HDAC1 and HDAC2. To identify HDAC2-selective inhibitors, we focused on kinetic parameters, namely disassociation rate (k_off) and residence time (t), and we have identified a kinetically selective HDAC2 inhibitor. The kinetically selective HDAC2 inhibitor showed potent memory-enhancing activity in in vivo studies. KDM5C has been proposed as an oncogene in prostate cancer cells and is also associated with neurological disorders such as Huntington’s disease. However, its precise pathophysiological roles remain unclear. Therefore, KDM5C inhibitors are of interest as biological tools for studying the functions of KDM5C, as well as candidate therapeutic agents for neurological disorders. Recently, we have identified a KDM5C-selective inhibitor by using a modified in situ click chemistry. Interestingly, the KDM5C-inhibitor showed potent antidepressant activity in in vivo studies. In this symposium, the discovery of these epigenetic inhibitors targeting neurological disorders will be presented.		2021/9/30　14:00～16:00　ZOOM C会場 S6-4 ヒトiPS 細胞技術を用いた神経毒性評価法の開発 Development of in vitro neurotoxicity assessment using human iPSC technology ^○諫田泰成国立医薬品食品衛生研究所 ^○Yasunari Kanda Division of Pharmacology, National Institute of Health Sciences Epidemiologic evidence has demonstrated associations between prenatal exposure to chemicals and the occurrence of attention-deficit/hyperactivity disorder in children. The developing brain in the fetal and infantile periods is vulnerable to chemicals, compared with that in adults. Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) have been evaluated animal testing. However, the large cost and time required for DNT testing. It is necessary to develop alternative in vitro methodologies that can reliably support identification of chemicals with DNT potential. Because human iPSCs are considered to cover key neurodevelopmental processes and reproduce different windows of exposure during human brain development, we have developed in vitro DNT assay system using human iPSC technology. Structural toxicity was assessed by differentiation capability of human iPSCs. We found that DNT-positive chemicals inhibited neural differentiation via mitofusin, which plays a role in mitochondrial dynamics. In addition, functional toxicity was assessed using network activities recorded by multi-electrode array system in iPSC-derived neurons. DNT-positive chemicals inhibited spikes and network bursts in iPSC-neurons. In this symposium, we would like to talk about the current status and future perspectives of in vitro neurotoxicity assessment using human iPSC technology.