公募シンポジウム
精神・神経疾患発症に関わるシグナル伝達機構解析の新展開 |
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| 7月8日（土） 16:00-18:00 Room E
3SY⑧-1
神経線維腫症の病態の発症に関わる新規のシグナル伝達機構の解明
Novel small GTPase signaling pathway involved in pathogenesis of neurofibromatosis
多胡 憲治1, 多胡 めぐみ2
1. 群馬大学大学院保健学研究科, 2. 慶應義塾大学薬学部衛生化学講座
Kenji Tago1, Megumi Funakoshi-Tago2
1. Fac. of Med. Sch. of Health Sci., Gunma Univ., 2. Div. of Hyg. Chem., Fac. of Pharm., Keio Univ.
The genetic mutation in NF1 (Neurofibromin), a suppressor of Ras small GTPase, causes neurofibromatosis type I (also called as NF1 or Recklinghausen disease). In this study, we attempted to clarify novel signaling pathway involved in pathogenesis of NF1. First, we found that Brefeldin A, known as an inhibitor for a small GTPase Arf, strongly inhibited the activation of ERK and Akt. Furthermore, the Brefeldin A caused the cell cycle arrest in NF1 cells at the G0/G1 phase and induced cell death. In cells treated with Brefeldin A, the expression of cyclin D1 and the phosphorylation of Rb were strongly diminished. Furthermore, the expression level of p27Kip1 protein was significantly enhanced. Finally, we found that the expression of miR-222-3p, a miRNA targeting p27Kip1 mRNA was drastically diminished by Brefeldin A. It was found that antisense RNA against miR-222-3p remarkably increased the expression level of p27Kip1 protein. As described above, we revealed that Ras signaling is enhanced by Arf in NF1 cells. Furthermore, miR-222-3p promotes cell proliferation by regulating the expression level of p27Kip1 protein. | | 7月8日（土） 16:00-18:00 Room E
3SY⑧-2
精神疾患発症機序解明に向けた維持型DNAメチル化酵素DNMT1の神経細胞における機能解析
Functional analysis of DNMT1 in neurons for understanding the molecular mechanism of psychiatric disorders
波平 昌一1, 木村 文香2, 齋藤 裕3, 新木 和孝4, 平野 和己1, 中島 欽一5
1. 産総研 バイオメディカル, 2. 大阪精神医療センター こころの科学リサーチセンター, 3. 産総研 人工知能研究センター, 4. 産総研 細胞分子工学, 5. 九州大院 医 応用幹細胞医科学
Masakazu Namihira1, Ayaka Kimura2, Yutaka Saito3, Kazutaka Araki4, Kazumi Hirano1, Kinichi Nakashima5
1. Biomed. Res. Inst., AIST, Japan, 2. Devel. of Novel Dx. and Tx. Div., OPRC, Japan, 3. AIRC, AIST, Japan, 4. Cell. and Mol. Biotech. Res. Inst., AIST, Japan
DNA methylation in the brain have become considered to be implicated in psychiatric disorders, since environmental factors, in addition to genetic factors, have appeared to be associated with such diseases. It has been reported that missense mutations in DNA methyltransferase 1 (DNMT1) were suggested to contribute to the risk of schizophrenia. Thus, it is conceivable that the dysfunction of DNMT1 is one of the causal problems of psychiatric disorders, but its detailed function and role in post-mitotic neurons still remains elusive. We found that the dendritic complexity in dentate gyrus (DG) neurons of neuron-specific Dnmt1 conditional knock-out (cKO) mice was increased compared to that in neurons of control mice. Moreover, Dnmt1 cKO mice exhibited a symptom of hyperactivity in behavioral analysis, especially the open field test and light/dark transition test. DNA methylome analysis shows preferential hypomethylation of neuron-specific enhancers together with the slight genome-wide hypomethylation in DNMT1-deficient neurons directly isolated from DG of Dnmt1 cKO mice. These results suggest that DNMT1 in post-mitotic neuron play a crucial role in proper neuronal development and function via DNA methylation on neuronal enhancers. In this symposium, we would like to introduce further details of the findings. | | 7月8日（土） 16:00-18:00 Room E
3SY⑧-3
拡がるオリゴデンドロサイト疾患と治療標的候補分子のハンティング
Hypomyelinating leukodystrophies and their candidate molecules for therapeutic targets
山内 淳司1,2,3, 宮本 幸1,2
1. 東京薬科大学, 2. 国立成育医療研究センター, 3. 東京都医学研
Junji Yamauchi1,2,3, Yuki Miyamoto1,2
1. Tokyo University of Pharmacy and Life Sciences, 2. NICHD, 3. TMiMS
Pelizaeus-Merzbacher disease (PMD) is a degenerative central nervous system disease with an etiology of 1 in 200,000-500,000 people. The gene responsible for PMD is plp1 encodes a protein molecule responsible for myelin transmembrane junctions. In recent years, with the rapid progress of next-generation gene sequencing technology, new genes responsible for central nervous system degenerative disease, which was once thought to be a similar disease to PMD, called hypomyelinating leukodystrophy (HLD), has been identified. On the other hand, there are “many” unclear points about the causal relationship between their responsible genes and their mechanisms that trigger the pathology. So far, we have developed a co-culture technique that can reproduce the degeneration of neuronal tissue caused by plp1 and other gene mutation, and have identified some therapeutic molecular targets including certain kinases as well as candidate therapeutic RNA and chemicals. The effect as a therapeutic candidate molecule was also confirmed in PMD and HLD model mice. Here, we would like to introduce researches on the potential molecular mechanisms of onset and its treatment methods, at least in vitro, for a large number of emerging HLD-responsible genes. | | 7月8日（土） 16:00-18:00 Room E
3SY⑧-4
オリゴデンドロサイト分化に関わる新規シグナル伝達機構と精神疾患
Novel signal transduction mechanisms involved in oligodendrocyte differentiation and psychiatric disorders
宮田 信吾1, 清水 尚子1, 石野 雄吾1, 遠山 正彌1,2
1. 近畿大学 東医 分子脳科学, 2. 大阪府立病院機構
Shingo Miyata1, Shoko Shimizu1, Yugo Ishino1, Masaya Tohyama1,2
1. Div. of Mol. Brain Res., Ins. Tra. Asian Med., Kindai Univ., Osaka, Japan, 2. Osaka Pref. Hospital Org., Osaka, Japan
Oligodendrocytes (OLs), the myelin-forming cells in the central nervous system (CNS), undergo morphological differentiation characterized by elaborated branched processes to enwrap neuronal axons. However, the basic molecular mechanisms underlying OLs morphogenesis remain unknown. This review first describes the essential roles of Nuclear Distribution E Homolog 1 (NDE1), a dynein cofactor, in OLs morphological differentiation. Second, protein arginine methylation has been recognized as one of the critical posttranslational modifications for advanced protein functions, mediated by protein arginine methyltransferases (Prmts). However, Prmts detailed function in the CNS, particularly in OLs, remains largely unexplored. We showed one of the Prmts, Carm1 activity, is required for the appropriate formation of myelin processes and myelin sheaths around neuronal axons and the induction of the clustering of Caspr, a node of the Ranvier structural molecule. Third, major depressive disorder is considered a multifactorial disease susceptible to environmental and genetic factors; however, pathogenesis at the molecular level is still unknown. We found activating the PDK1-SGK1-NDRG1 cascade in OLs may play a key role in upregulating adhesion molecules and increasing the excess arborization of OLs processes in the corpus callosum of chronically stressed mice. | |
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