公募シンポジウム６：希少性・難治性疾患の改善にかかわる新しいシグナル伝達経路
Symposium6 : Newly-occurring signaling pathway ameliorating rare and refractory diseases |
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| 2020/9/10 17:50～18:10 Zoom A
SY6-01
細胞接着タンパク質による髄鞘関連疾患に関わる小径軸索髄鞘化の制御
Cell Adhesion Proteins Regulate Myelination of Small Caliber Axons Critically Involved in Myelin-related Diseases
*鈴木 喜晴1
1. 東京医科歯科大学大学院医歯学総合研究科 遺伝子細胞検査学分野
*Nobuharu Suzuki1
1. Dept. of Mol. and Cell. Biol., Grad. Sch. of Med. and Dent. Sci., Tokyo Medical and Dental University
In the CNS, the axonal tracts with various caliber sizes are myelinated by oligodendrocytes and function as high-velocity ways for nerve signals. Smaller caliber axons are more vulnerable with demyelination and/or axonal degeneration in myelin-related diseases, such as multiple sclerosis and Pelizaeus-Merzbacher disease/spastic paraplegia 2. However, the molecular and cellular mechanisms to regulate the myelination of small caliber axons are poorly understood. In recent years, cell adhesion proteins and related signaling proteins have been identified as regulators of myelination of smaller axons. Here, we report that teneurin-4 (Ten-4), a cell adhesion protein, is a key player in myelination of small caliber axons in the CNS. In Ten-4 deficient mice, hypomyelination of small diameter axons was observed in the CNS tissues, and an onset of the defect was the stage that myelination began. Further, an electron microscopy analysis revealed that the adhesion of oligodendrocyte processes to axonal surfaces was reduced in the Ten-4 deficient tissue. In additional in vitro experiments, we found that oligodendrocytes adhesion through Ten-4 and the other teneurin family members promoted myelination on axon-mimicking nanofibers, which required the activation of Src kinase. We finally examined whether Ten-4 regulated the development of type I/II oligodendrocytes, since type I/II oligodendrocytes among four types (I to IV) were known to myelinate small diameter axons. As a result, type I/II oligodendrocytes were significantly reduced in Ten-4 deficient mice. Our findings suggest that cell adhesion by Ten-4 is required for the myelination of small caliber axons via the regulation of type I/II oligodendrocytes.
| | 2020/9/10 18:10～18:30 Zoom A
SY6-02
拡がるペリチェウス・メルツバッヘル病を改善する新しい分子経路
New molecular pathways to improve the expanding Pelizaeus– Merzbacher disease
*山内 淳司1,2、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研究所
*Junji Yamauchi1,2, Yuki Miyamoto1,2
1. TUPLS, 2. NICHD
Pelizaeus–Merzbacher disease is a central nervous system degenerative disease with a frequency of 1 in 200,000 to 500,000. The gene responsible for PMD is plp1, which encodes a molecule that has a four-transmembrane structure and is responsible for inter-membrane junctions. In recent years, with the rapid advancement of next-generation gene sequence analysis technology, genes responsible for central nervous degeneration disease of hypomyelinating leukodystrophy (HLD), which was once considered a similar disease to PMD, have been newly identified, and up to 19 mutations in the responsible gene or its candidate genes have been reported. We have constructed a pathological co-culture system that can reproduce the development process of oligodendrocytes and neurons in vitro. We are applying these technologies and results to elucidate the pathological mechanism of each HLD, and are conducting not only in vitro studies but also in vivo studies using PMD and new HLD model mice. In this issue, I would like to report these new findings as well as new molecular pathways involved in the treatment.
| | 2020/9/10 18:30～18:50 Zoom A
SY6-03
精神遅滞原因遺伝子産物 Cereblon の関わる転写制御機構
Transcriptional Regulation by Cereblon, a Gene Product Responsible for Intellectual Disability
*澤村 直哉1,2
1. 早稲田大学 ナノ・ライフ創新研究機構、2. 早稲田大学 グリーン・コンピューティング・システム研究機構
*Naoya Sawamura1,2
1. Research Organization for Nano & Life Innovation, Waseda University, 2. Green Computing Systems Research Organization, Waseda University
Cereblon (CRBN) is a protein consisting of 442 amino acids identified in the analysis of families exhibiting intellectual disability (ID). Two actual cases have been reported so far in which the function of CRBN may have failed due to mutations, resulting in ID. A nonsense mutation, R419X CRBN, has been reported to lead to mild ID (Higgins et al. Neurology 63, 1927-1931 (2004)), while the C391R mutation leads to the development of severe ID (Sheereen et al. J Med Genet 54, 236–240 (2017)). CRBN has been shown to function in the cytoplasm as an E3 ubiquitin ligase while having a different function in the nucleus. We found that CRBN regulates the expression of its downstream pro-enkephalin (PENK) gene through the transcription factor Ikaros (Wada et al. BBRC 477, 388-394 (2016)). We also found that Ohgata, the Drosophila ortholog of CRBN are mainly localized in the nucleus and identified it as a novel regulator of insulin-dependent organismic growth in Drosophila (Wakabayashi et al. JBC 291, 25120-25132 (2016)). In this talk, I will focus on the molecular mechanism of C391R CRBN-induced severe ID, mainly focusing on the transcriptional regulation by CRBN.
| | 2020/9/10 18:50～19:10 Zoom A
SY6-04
リポタンパク質受容体LRP1シグナルによる視神経保護
Protection against optic nerve degeneration by low density lipoprotein receptor-related protein 1 signaling
*林 秀樹1、高木 教夫1
1. 東京薬科大学
*Hideki Hayashi1, Norio Takagi1
1. Tokyo University of Pharmacy and Life Sciences
Lipid homeostasis in the central nervous system is maintained mainly by glia. Cholesterol and other lipids are transported from glia to neurons by glia-derived lipoproteins. Apolipoprotein E-containing lipoprotein (E-LP) is a major lipoprotein in lipid transport and metabolism of the central nervous system. It has been reported that glia are activated in response to nerve injury and then significantly increase secretion of E-LPs. However, it is unknown what E-LPs play under pathological conditions. We previously showed that E-LPs protected primary cultured retinal ganglion cells from apoptosis led by trophic factor-withdrawal, glutamate-induced excitotoxicity and oxidative stress, and an intracellular protective signal was mediated by the low density lipoprotein receptor-related protein 1 (LRP1). Furthermore, intravitreal injection of E-LPs attenuated optic nerve degeneration in mouse and rat models of glaucoma without high intraocular pressure. In addition, alpha 2-macroglobulin, one of ligands of LRP1, secreted from glia interfered the protective effect of E-LPs against glutamate-induced excitotoxicity in primary cultured retinal ganglion cells. On the other hand, E-LPs did not protect primary cultured cortical neurons from glutamate-induced excitotoxicity because intracellular domain of LRP1 was cleaved after the excitotoxicity. We found that the intracellular cleavage of LRP1 was mediated by a calcium-dependent endoprotease furin. These findings indicate that significant roles of an LRP1 signaling on neuronal survival and a potential therapeutic target for optic nerve degeneration in glaucoma without high intraocular pressure.
| | 2020/9/10 19:10～19:30 Zoom A
SY6-05
オートファジー抑制因子Rubiconの発現抑制によるポリグルタミン病の改善
Therapeutic effects of Rubicon knockdown in a Drosophila model of polyglutamine disease.
*鈴木 マリ1
1. 東京都医学総合研究所
*Mari Suzuki1
1. Tokyo Metropolitan Institute of Medical Science
Accumulation of pathogenic misfolded proteins is thought to be a common mechanism of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and polyglutamine (polyQ) diseases. These diseases are thought to share a common molecular pathogenesis involving accumulation of misfolded proteins and the autophagy-lysosome degradation system may have therapeutic potential against these diseases, because it can degrade even large protein aggregates. We focused on one of few negative regulators of autophagy, Rubicon (Run domain Beclin-1 interacting and cysteine-rich containing protein), and examined whether suppression of Rubicon shows beneficial effects on polyQ disease Drosophila model. Knockdown of Rubicon in neurons dramatically suppressed locomotor dysfunction and shortened lifespan of polyQ-expressing flies. Rubicon knockdown markedly reduced polyQ inclusion bodies in the brain, which is accompanied with no change in the polyQ mRNA level, suggesting that increased autophagic activity by dRubicon knockdown may lead misfolded polyQ proteins to be degraded. Moreover, we found that Rubicon is associated with the physiological aging, which is known to be a significant risk factor for neurodegenerative diseases. The expression of Rubicon increased in aged animals and knockdown of Rubicon extends lifespan in wild-type flies and worms. Our results suggest that suppression of autophagic activity by Rubicon is one of signatures of aging, and our study also provide basic insights into the possibility of Rubicon as a molecular target for treatment of misfolded protein-associated neurodegenerative diseases.
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