若手道場

若手道場神経系疾患と治療

7月6日（木）　15:20-16:20　Room H 1W⑥-1 CCT4はタウの蓄積を抑制しタウによる神経細胞死を緩和する CCT4 suppresses tau accumulation and ameliorates tau-induced neurodegeneration in Drosophila 榎本　美優東京都立大学 Miyu Enomoto Tokyo metropolitan university Abnormal accumulation of microtubule-associated protein tau is thought to cause neuron loss in a group of neurodegenerative diseases. Tau regulates microtubule stability in the axon, however, tau is abnormally phosphorylated and undergoes conformational changes in disease pathogenesis. The chaperonin containing TCP-1 (CCT) is an oligomeric chaperone required for the folding of newly synthesized tubulin and actin proteins. It is also reported to prevent aggregation of mutant Huntingtin and neuroprotective. Although the subcellular localization and functions of CCT overlap with those of tau proteins, its roles in tau abnormality are not fully understood. Here we report that CCT subunits, CCT2 and CCT4, affect tau toxicity differently. By using Drosophila expressing human tau, we found that overexpression of CCT4 reduced tau phosphorylation in the microtubule-binding repeat and ameliorated tau-induced neurodegeneration. In contrast, overexpression of CCT2 enhanced tau-induced neurodegeneration. Knockdown of CCT1 or CCT2 did not affect tau phosphorylation, suggesting that the effects of CCT4 is mediated via its function as a monomer but not as a CCT oligomeric complex.Our results suggest novel roles of CCT2 and CCT4 monomers in tau metabolism and toxicity. Further studies of their interaction will advance our understanding of how tau abnormality occurs in disease pathogenesis.		7月6日（木）　15:20-16:20　Room H 1W⑥-2 optic nerve crushモデルマウスの視神経伸長に対するジオスゲニンの効果 Effects of diosgenin on optic nerve growth in an optic nerve crush model mouse 渋江　省吾, 東田　千尋富山大学　和漢研・神経機能学領域 Shogo Shibue, Chihiro Tohda Sec. of Neuromedical Science, Inst. of Natural Medicine, Univ. of Toyama, Japan Glaucoma is a major cause of irreversible blindness worldwide, and is evoked by degeneration and loss of retinal ganglion cells (RGC). Our laboratory previously found axonal regeneration activity of diesgenin. Therefore, this study aimed to investigate effects of diosgenin on optic nerve growth in an optic nerve crush model.Based on our previous data showing that intravitreal injection of Diosgenin increased optic nerve density in the optic nerve crush model, this study aims to investigate oral treatability and potency of Diosgenin.At first, we evaluated brain penetration of diosgenin after p.o. administration. Diosgenin was detected in the retina, the optic nerve and whole brain at least 6h after p.o. administration.Immediately after optic nerve crushing, Diosgenin or vehicle solution was administered orally for 3 weeks. The number of retinal ganglion cells and optic nerve termination to the lateral geniculate nucleus were increased by Diosgenin. Diosgenin treatment to primary cultured RGC for 4 days significantly enhanced axonal length. The mechanism of Diosgenin for axonal growth of RGC is under investigation.

7月6日（木）　15:20-16:20　Room H 1W⑥-3 SUMO化修飾阻害はマウス脳内出血後の血腫除去と病態回復を低下させる Inhibition of SUMOylation impairs hematoma clearance and neurological recovery after intracerebral hemorrhage in mice 木下　慶大¹, 倉内　祐樹¹, 関　貴弘^1,2, 香月　博志¹ 1. 熊本大学大学院薬薬物活性学, 2. 姫路独協大　薬　薬理 Keita Kinoshita¹, Yuki Kurauchi¹, Takahiro Seki^1,2, Hiroshi Katsuki¹ 1. Dept. of Chemico-Pharmacol., Grad. Sch. of Pharm. Sci., Kumamoto Univ. Intracerebral hemorrhage (ICH) is a type of stroke that is triggered by bleeding in the brain parenchyma, followed by development of hematoma toxicity, inflammation, and oxidative stress. SUMOylation is one of post-translational protein modifications that is caused by the covalent binding of the small ubiquitin-like modifier (SUMO) peptide. Although SUMOylation has been reported to play neuroprotective roles in ischemic stroke, the role of SUMOylation in the pathology of ICH remains unclear. Here we investigated the effect of TAK-981, an inhibitor of SUMOylation, in a mouse model of ICH. Intracerebroventricular (ICV) injection of TAK-981 (4 nmol) decreased the level of SUMO2/3 conjugation. And, TAK-981 injection before ICH induction decreased the survival rate and delayed recovery from weight loss and neurological deficits. Moreover, residual hematoma size was larger, whereas the injury volume (neuronal loss) was not changed in TAK-981-injected group compared to vehicle-treated group. Furthermore, the expression of CD36, a scavenger receptor involved in erythrophagocytosis, in microglia/macrophages was significantly lower in TAK-981-injected group. These results indicate that the inhibition of SUMOylation suppresses hematoma clearance via regulation of CD36 expression after ICH. We further examine how SUMOylation regulates CD36 expression and affects the pathology of ICH.		7月6日（木）　15:20-16:20　Room H 1W⑥-4 新規誘導法の組み合わせにより観察可能となったiPS細胞由来神経、アストロサイト共培養系におけるアルツハイマー病様表現型 Combination of Novel Methods to Induce Neurons and Astrocytes from iPSCs Elicited Alzheimer's Disease-like Phenotypes Sopak Supakul, 前田　純宏, 岡野　栄之慶應義塾大学生理学教室 Sopak Supakul, Sumihiro Maeda, Hideyuki Okano Dept. of Physiology., Keio Univ., Tokyo, Japan Induced Pluripotent Stem Cells (iPSCs) technology enabled disease modeling using patient’s cells differentiated into various cell types. However, most of the cellular disease models from iPSCs are composed of single-cell types, in which the cells are often immature. Multifactorial diseases like Alzheimer’s disease (AD) is not caused by the dysfunction of single-cell type but by multi-cell types. In order to recapitulate such pathogenesis, the culture model comprised of several cell types is needed. Here, we established the co-culture model of astrocytes and neurons induced by identical iPSCs. The cell-to-cell interaction was confirmed by the treatment of the excitatory amino acid transporter inhibitors, which increased neuronal activities. Furthermore, we found that the co-culture of them increased the branching of the astrocyte processes and the number of GFAP-positive astrocytes. In addition, in the co-culture of familial AD (APP V717L mutation) iPSC-derived neurons and astrocytes, an astrogliosis-like phenotype and astrocytic hypertrophy were observed. The astrogliosis-like phenotype was ameliorated by 17β-estradiol which reduction is involved in the pathogenesis of AD. This co-culture model of neurons and astrocytes derived from the iPSCs is a useful tool for the disease modeling of neurodegenerative diseases and the examination of the intervention effects in vitro.