公募シンポジウム７：脂質が制御する神経機能
Symposium7 : Neural functions regulated by lipid signaling |
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| 2020/9/10 17:50～18:10 Zoom B
SY7-01
神経炎症における生理活性脂質 ― 創薬への応用と腸脳相関
Bioactive lipids in the neuroinflammation, application to drug discovery and gut-brain interactions
*吉川 圭介1
1. 埼玉医科大学
*Keisuke Yoshikawa1
1. Saitama Medical Univ.
Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure. Previously we reported that cPA suppresses cuprizone-induced demyelination and motor dysfunction. We investigated whether 2-carba-cPA (2ccPA), chemically synthesized and metabolically stabilized derivatives of cPA, suppresses pathology in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination, which are mouse models of multiple sclerosis (MS). 2ccPA suppressed cuprizone-induced demyelination and motor dysfunction, and remitted the clinical symptoms of EAE, suggesting that 2ccPA may be a promising seed compound for MS.
PUFA receptor GPR120 is expressed in intestinal tissues. We previously reported that GPR120 senses PUFA and mediates the secretion of an incretin, glucagon-like peptide-1 (GLP-1), which promotes insulin secretion. Dysfunction of GPR120 results in obesity in both mice and humans. Also, we reported that a surge prostaglandin D2 (PGD2) production and microglial activation provoked neuroinflammation in the hippocampus. To reveal the relationship between PGD2-microglia-provoked neuroinflammation and intestinal GPR120, we investigated neuroinflammation and neuronal function in GPR120KO mice. We discovered PGD2-microglia-provoked neuroinflammation and neurodegeneration (declines in neurogenesis, hippocampal volume, and cognitive function) in GPR120KO mice, which could be attenuated by inhibition of PGD2 production. Peripheral administration of GLP-1 analogue, liraglutide, reduced hippocampal PGD2 production and attenuated neurological phenotypes in GPR120KO mice. These observations may reveal the presence of the novel gut-brain interactions, in that the signaling of dietary PUFA is sensed by GPR120, converted into incretin bioactivity, and exerted neuroprotective effects via suppression of PGD2-microglia-provoked neuroinflammation in the hippocampus.
| | 2020/9/10 18:10～18:30 Zoom B
SY7-02
網羅的脂質解析によるクリスタリン網膜症の病態解明および治療法開発
Lipidomic analyses to determine the mechanisms and novel therapeutic methods for crystalline retinopathy
*池田 華子1
1. 京都大学医学部附属病院
*Hanako Ohashi Ikeda1
1. Kyoto University Hospital
Retina contains abundant docosahexaenoic acid. Retinal pigment epithelium (RPE) is involved in the phagocytosis and recycling of the outer segment of photoreceptor cells and supply of lipids to the photoreceptors. Thus, RPE is a highly active tissue involved in lipid metabolism. Abnormal lipid metabolism in RPE has been associated with the pathophysiology of some intractable retinal diseases, including age-related macular degeneration and degenerative retinal diseases.
Bietti's crystalline dystrophy (BCD) is an autosomal recessive, progressive chorioretinal degenerative disease. RPE cells are impaired in patients with BCD. However, the underlying mechanisms of RPE cell damage have not been elucidated, and treatments for the disease have not been developed.
Using BCD patient-specific induced pluripotent stem cells (iPSC), we successfully generated a human in vitro model of BCD, BCD patient-specific iPSC-RPE cells. Lipidomic analyses of the iPSC-RPE cells revealed that free cholesterol accumulation caused RPE cell damage and subsequent cell death through the inductions of lysosomal dysfunction and autophagy flux impairment in BCD-affected cells. Cyclodextrins reduce free cholesterol and avoid damage. Intracellular free cholesterol reduction by cyclodextrins and so on might be therapeutic for patients with BCD.
| | 2020/9/10 18:30～18:50 Zoom B
SY7-03
パーキンソン病病態に関与するリン脂質変化
Alteration of phospholipids associated with the etiology of Parkinson's disease
*今居 譲1
1. 順天堂大学
*Yuzuru Imai1
1. Juntendo University
The aggregation of a presynaptic protein α-Synuclein is the cause of Lewy body (LB) diseases including Parkinson's disease (PD). Mutations of PLA2G6, which codes a phospholipase A2, cause PD and neurodegeneration with brain iron accumulation (NBIA), the pathology of which shows marked accumulation of LBs, neuronal inclusions of α-Synuclein. The pathological evidence suggests the alteration of phospholipids leads to α-Synuclein aggregation.
To understand the pathogenesis of α-Synuclein aggregation by phospholipid alteration, we generated PLA2G6-deficient Drosophila. PLA2G6-/- flies exhibited bang sensitivity, sensitivity to high temperature, vacuolization of brain tissues and motor defects. Moreover, the shortening of phospholipid acyl-chain and resultant ER stress were observed. The neurodegenerative phenotypes and acyl-chain shortening were suppressed by the administration of linoleic acid or introduction of human wild-type PLA2G6, but not a pathogenic PLA2G6 mutant. Another NBIA causative gene, C19orf12, the pathology of which also shows marked accumulation of LBs, encodes a mitochondrion/ER-resident small protein that maintains the mitochondria-associated ER membranes (MAM). Overexpression of C19orf12 in PLA2G6-/- flies suppresses the alteration of phospholipid acyl-chain shortening and neurodegenerative phenotypes by the PLA2G6 loss.
The expression of α-Synuclein in PLA2G6-/- flies exhibited a prominent aggregation of α-Synuclein in the brain. An artificial liposome assay revealed that the phospholipid acyl-chain shortening weakened the association of α-Synuclein with lipid membrane. Our results suggest that an increased probability of the membrane-unbound form of α-Synuclein elevates the risk of α-Synuclein aggregation.
| | 2020/9/10 18:50～19:10 Zoom B
SY7-04
慢性ストレスによる脂質メディエーターの産生機序と情動変容における役割
The production and roles of lipid mediators in repeated stress-induced behavioral changes
*北岡 志保1、聶 翔1、篠原 正和1、成宮 周2、古屋敷 智之1
1. 神戸大学、2. 京都大学
*Shiho Kitaoka1, Xiang Nie1, Masakazu Shinohara1, Shuh Narumiya2, Tomoyuki Furuyashiki1
1. Kobe University, 2. Kyoto University
Social and environmental stress is a risk factor for various stress-related disorders such as major depression. Although stress response is essential as a survival mechanism, excess or prolonged stress induces emotional changes and cognitive decline.
It was reported that inflammation-related molecules including prostaglandin (PG) E2 are increased in blood from patients with major depression. Furthermore, celecoxib, a cyclooxygenase inhibitor, is known to enhance the therapeutic effect of an antidepressant drug. There is a high comorbidity between depression and chronic inflammatory diseases. These facts suggest the relation between depression and inflammation. However, it remains unclear whether inflammation causes depression.
We are studying the roles of inflammation-related molecules in stress-induced behavioral changes using repeated social defeat stress, an animal model of depression. Since COX-1 and COX-2 are crucial for producing PGs, we examined whether or which COX is involved in repeated stress-induced behavioral change. COX-1, which is expressed in microglia, was required to induce repeated stress-induced behavioral change, suggesting the possible roles of lipid mediators and microglia in pathology of depression. Based on these findings, we demonstrated that repeated stress activates microglia through Toll-like receptors, leading to stress-induced behavioral change. In this presentation, I will talk about the molecular mechanisms underlying repeated stress induces neuroinflammation. And I'd like to introduce the latest findings regarding repeated stress-induced production of lipid mediators in the brain as well as peripheral organs.
| | 2020/9/10 19:10～19:30 Zoom B
SY7-05
アストロサイトS1P受容体を標的とした多発性硬化症治療戦略
Sphingosine 1-phosphate receptor modulators for treatment of multiple sclerosis
*木原 泰行1
1. サンフォードバーナムプリビス医学研究所
*Yasuyuki Kihara1
1. Sanford Burnham Prebys Medical Discovery Institute
Sphingosine 1-phosphate is a bioactive lipid that binds to 5 cognate G protein-coupled receptors (S1P1-5). Fingolimod is a sphingosine analog that is metabolized by sphingosine kinases (SPHK1/2) to form fingolimod phosphate (fingolimod-P). Fingolimod was approved by United States Food and Drug Administration in 2010 for the treatment of relapsing-remitting multiple sclerosis (MS). The mechanism of action (MOA) of fingolimod was proposed to sequestrate pathogenic lymphocytes from circulation to secondary lymphoid organs via down-regulation of the cell surface expression of S1P1. Because S1P1 is abundant in astrocytes and fingolimod is accumulated in the CNS, we have studied the central nervous system (CNS)-mediated MOA of fingolimod. In this presentation I introduce a novel functional astrocyte subset that we named “ieAstrocyte.” The ieAstrocytes was identified by unbiased c-Fos activity screen in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). I also introduce a novel linkage between S1P signaling and vitamin B12 systems, which was identified by nuclear RNA-sequencing of ieAstrocytes.
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