若手道場

若手道場神経変性疾患・認知症

7月6日（木）　10:00-11:00　Room H 1W②-1 骨格筋萎縮に伴って分泌されるヘモペキシンは正常マウスの認知機能を低下させる Skeletal muscle atrophy-derived hemopexin induced memory impairment in normal mice 井城　綸沙, 東田　千尋富山大学　和漢医薬学総合研究所　神経機能学領域 Tsukasa Iki, Chihiro Tohda Sec. of Neuromedical Science, Inst. of Natural Medicine, Univ. of Toyama, Japan Decline in physical movement with aging may be a cause of age-associated lowering of the brain function. Our previous study revealed that skeletal muscle atrophy shifted the onset of memory dysfunction earlier without increasing the deposition of Aβ in young Alzheimer´s disease (AD) mice. The atrophied muscles secreted hemopexin. Moreover, i.c.v. infusion of hemopexin was induced cognitive impairment in young AD and wild-type mice. This indicates the possibility that hemopexin is directly involved in the onset of cognitive impairment. This study aimed to elucidate the onset of memory impairment by skeletal muscle atrophy in normal mice and its molecular mechanisms.The bilateral hindlimbs of young mice (ddY, male, 12 weeks of age) were immobilized by cast-attachment for 14 days. Object recognition memory in the cast-attached mice was impaired after the cast-attachment. Conditioned media (CM) of muscle organ culture was collected. Hemopexin levels in the CM, skeletal muscle and hippocampus were increased in cast-attached mice. Extracellular vesicle (EV) was isolated from CM using column affinity methods. It was shown that the concentration of EVs was increased in cast-attached mice. We are investigating the amount of hemopexin in EVs and its transfer to the brain. These evidences indicate that skeletal muscle-derived hemopexin induces cognitive impairment in young normal mice.		7月6日（木）　10:00-11:00　Room H 1W②-2 Microtubule affinity-regulating kinase 4 affects glucose transporter localization and neuronal energy metabolism リムリンガン　ソフィア　ジョビエン, 斎藤　太郎, スルタナフメトフ　グリ, 淺田　明子, 安藤　香奈絵理学研究科生命科学専攻東京都大学、東京、日本 Sophia Jobien Limlingan, Taro Saito, Grigorii Sultanakhmetov, Akiko Asada, Kanae Ando Tokyo Metropolitan University, Tokyo, Japan Neurodegenerative diseases such as Alzheimer’s disease are characterized by complex irregularities such as glucose metabolic dysfunctions. Microtubule-affinity regulating kinase 4 (MARK4) regulates microtubule dynamics via phosphorylation of microtubule-associated proteins and is upregulated in Alzheimer’s disease brains. MARK4 is a member of the AMP-activated protein kinase-related family and has been reported to regulate glucose metabolism in the peripheral tissues. However, whether and how MARK4 regulates energy metabolism in neurons is not well understood. Here we report that MARK4 regulates glucose uptake in neurons. We found that MARK4 knockdown by siRNA lowers glucose uptake in primary neurons. In HEK293 cells transfected with the primary neuronal glucose transporter 3 (GLUT3), co-expression of MARK4 reduced the distribution of GLUT3 to plasma membrane and caused its accumulation in the cytosol. In MARK4 null mutant mice, the total expression level of GLUT3 was similar to the wild-type, while immunostaining of GLUT3 showed punctate patterns, suggesting that the distribution of GLUT3 is disrupted. Our results suggest that MARK4 affects neuronal glucose metabolism by regulating GLUT3 trafficking in neurons.

7月6日（木）　10:00-11:00　Room H 1W②-3 HLAクラスII分子によるアルファシヌクレインの細胞外輸送 Extracellular transportation of α-synuclein by HLA class II molecules 大薗　達彦, 木村　康義, 池中　建介, 別宮　豪一, 望月　秀樹大阪大学医学部医学系研究科　神経内科学 Tatsuhiko Ozono, Yasuyoshi Kimura, Kensuke Ikenaka, Goichi Beck, Hideki Mochizuki Dept. of Neurology, Osaka University, Japan Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of α-synuclein aggregates in form of Lewy bodies. Genome-wide association studies have revealed that human leukocyte antigen (HLA) class II is a PD-associated gene, although the mechanisms linking HLA class II and PD remain elusive. Objective: We investigated whether HLA class II molecules transported intracellular α-synuclein to the outside of cells. Methods: Interactions between HLA class II molecules and α-synuclein as well as extracellular transportation of α-synuclein via HLA class II were analyzed in vitro. Results: HLA class II molecules and α-synuclein formed complexes and moved to the cell surface at various degrees among HLA-DR alleles. HLA-DR with a DRB501:01 allele, a putative PD-risk allele, substantially translocated normal and conformationally abnormal α-synuclein to the cell surface and extracellular vesicles. α-Synuclein/HLA class II complexes were found in A2058 melanoma cells, which express intrinsic α-synuclein and HLA-DR with DRB501:01. Conclusion: Our findings will expand our knowledge of unconventional HLA class II function from autoimmune diseases to neurodegenerative disorders, providing an insight into the association between the GWAS-prioritized PD-risk gene HLA-DR and α-synuclein.		7月6日（木）　10:00-11:00　Room H 1W②-4 中枢神経系におけるリゾホスホリパーゼ欠損は神経変性と筋萎縮を引き起こす Deficiency of lysophospholipases in the central nervous system leads to neurodegeneration and muscle atrophy 川口　舞^1,2, 笠原　浩二², 平林　哲也², 村上　誠¹ 1. 東京大学大学院　医学系研究科　健康環境医工学部門, 2. 東京都医学総合研究所　基礎医科学分野　細胞膜研究室 Mai Kawaguchi^1,2, Kohji Kasahara², Tetsuya Hirabayashi², Makoto Murakami¹ 1. Lab. of Microenv. Metab. Health Sci., Grad. Sch. of Med., Univ. of Tokyo, Tokyo, Japan, 2. Lab. of Biomemb., Dept. of Basic Med. Sci., Tokyo Metro. Inst. of Med. Sci., Tokyo, Japan Autosomal recessive mutations in genes encoding enzymes in the patatin-like phospholipase (PNPLA/iPLA₂) family lead to neurodegenerative diseases such as hereditary spastic paraplegia, infantile neuroaxonal dystrophy, and parkinsonism. PNPLA6 and PNPLA7 are structurally related phospholipase B/lysophosholipases that degrade membrane phosphatidylcholine and lysophosphatidylcholine to water-soluble glycerophosphocholine. To elucidate the physiological roles of these two lysophospholipases in the central nervous system (CNS), we generated CNS-specific Pnpla6/Pnpla7-double knockout mice under the Nestin promoter (Pnpla6/7^ΔNes). Despite normal appearance until 2 weeks of age, Pnpla6/7^ΔNes mice subsequently displayed progressive neurodegenerative muscular atrophy, with lower weight gain, muscle weakness, short lifespan, and broad neurodegeneration with gliosis, demyelination, and motor neuron loss. The neuromuscular junction in the quadriceps of Pnpla6/7^ΔNes mice exhibited age-related denervation. Lipidomics analysis revealed substantial reduction of myelin-related sphingolipids in Pnpla6/7^ΔNes CNS. These phenotypes were partially recapitulated in motor neuron- or astroglia-specific Pnpla6/7-deficient mice. These results suggest that the regulation of phospholipid catabolism by PNPLA6 and PNPLA7 is pivotal for the maintenance of neuronal homeostasis in the CNS.