若手道場 グループＤ
Wakate Dojo group D |
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| 2020/9/12 13:00～13:15 オンデマンドA-2
WD13
認知症発症を加速する骨格筋分泌性因子
A new unbeneficial myokine secreted from atrophied skeletal muscle accelerates the onset of Alzheimer's disease
*長瀬 綸沙1、東田 千尋1
1. 富山大学 和漢医薬学総合研究所 神経機能学領域
*Tsukasa Nagase1, Chihiro Tohda1
1. Toyoma Univ.
Several epidemiological and clinical studies show that exercise is positively associated with cognitive function and preventing Alzheimer's disease (AD). On the contrary, physical inactivity is known as one of risk factors for AD onset. Physical inactivity causes decreasing muscle mass. Several myokines are secreted by exercise, and the positive contribution is supposed. In contrast, unbeneficial myokines directly deteriorating cognitive function have not been identified. We hypothesized existence of unbeneficial myokines to accelerate AD onset, which are secreted from skeletal muscle at the physically inactivated state. Therefore, this study aimed to elucidate phenomenon and the mechanism of accelerating the onset of AD by skeletal muscle atrophy.To prepare a disuse muscle atrophy model, bilateral hindlimbs were immobilized by putting into casts for 14 days. Presymptomatic young age of 5XFAD mice were used. Object recognition memory in casted 5XFAD mice was impaired after casting although age matched wild-type and non-cast 5XFAD showed normal memory function. Hindlimbs were isolated for organ culture. Conditioned medium (CM) of muscles culture was separated on 2D-PAGE. Increased proteins in the CM of casted 5XFAD were identified by MALDI-TOF/MS analysis. Protein X (secret name due to patents) was significantly increased in CM. By ELISA, protein X in CM and in skeletal muscle was increased in casted 5XFAD. Furthermore, protein X in plasma was increased in casted 5XFAD mice. We supposed secreted protein X from skeletal muscle reach to and affect the brain, the memory function was evaluated after i.c.v. administration of protein X. Continuous i.c.v. infusion of protein X for 14 days during presymptomatic period induced memory deficit in young 5XFAD mice. We are now investigating whether skeletal muscle-specific knock down of protein X protects cast-inducing acceleration of the onset of AD. This study indicates that protein X is possible muscle atrophy-driven unbeneficial myokine to accelerate AD onset. Protein X is expected as a key molecule for predicting and preventing AD. | | 2020/9/12 13:20～13:35 オンデマンドA-2
WD14
DDAH1はオリゴデンドロサイトの分化を促進し、中枢神経系の再髄鞘化を促進する
The role of DDAH1 in oligodendrocyte differentiation during the central nervous system remyelination
*村松 永彬1,2、植田 尭子1、田辺 章悟1、鈴木 立紀2、村松 里衣子1
1. 国立精神・神経医療研究センター 神経研究所 神経薬理研究部、2. 東京理科大学大学院薬学研究科 疾病病態学・臨床薬理研究室
*Nagaaki Muramatsu1,2, Akiko Uyeda1, Shogo Tanabe1, Tatsunori Suzuki2, Rieko Muramatsu1
1. Dept. of Mol. Pharmacol., Nat. Inst. of Neurosci., NCNP, 2. Lab. of Pharmaco-pathol. and Clinical Pharmacol., Grad. Sch. of Pharmaceut. Sci., Tokyo Univ of Sci
Remyelination is a regenerative process to restore neurological dysfunction in demyelinating diseases such as multiple sclerosis. In the process, differentiation of oligodendrocyte precursor cells into oligodendrocytes spontaneously occur after demyelination. However, the cell intrinsic mechanism of oligodendrocyte differentiation during remyelination remains largely unknown. Here, we performed siRNA-based loss-of-function genomic screen on cultured oligodendrocytes, which was combined with phenotype-based screen using online compendium of human genes and genetic phenotypes. With this approach, dimethylarginine dimethylaminohydrolase 1 (Ddah1) was found as a novel regulator of oligodendrocyte differentiation. We performed RNA-seq analysis to investigate the change of gene expression by Ddah1 knock down in oligodendrocyte, and found that genes related to oligodendrocyte development were significantly enriched in the differently expressed genes. Pharmacological treatment with PD404182, a Ddah1 inhibitor, decreased the myelin basic protein expression in Olig2-positive oligodendrocytes-linage cells, further confirming the role of Ddah1 activity in oligodendrocyte differentiation. Moreover, intraventricular administration of PD404182 significantly attenuated the spontaneous remyelination of corpus callosum in cuprizone-induced demyelinated mice model. These results provide a novel therapeutic possibility for demyelinating diseases by modulating Ddah1 activity. | | 2020/9/12 13:40～13:55 オンデマンドA-2
WD15
ミクログリアの自己再生によるアレキサンダー病の抑制
Repopulation of microglia ameliorates the Alexander disease pathology
*小林 憲司1、繁冨 英治1、パラジュリ ビージェイ1、久保田 友人1、齋藤 光象1、田中 謙二2、池中 一裕3、小泉 修一1
1. 山梨大学大学院医学工学総合研究部 薬理学教室、2. 慶応義塾大学医学部 精神・神経科学教室、3. 生理学研究所 分子生理研究系 分子神経生理研究部門
*Kenji Kobayashi1, Eiji Shigetomi1, Bijay Parajuli1, Yuto Kubota1, Kozo Saito1, Kenji F Tanaka2, Kazuhiro Ikenaka3, Schuichi Koizumi1
1. Dept Neuropharmacol, Interdiscipl Grad Sch Med, Univ Yamanashi, 2. Dept Neuropsych, Keio Univ Sch Med., 3. Div Neurobiol and Bioinfo, NIPS
Alexander disease (AxD) is a rare neurodegenerative disorder resulting from the gain-of-dysfunction of astrocytes due to mutation of the GFAP gene, mostly expressed in astrocytes. Thus, AxD is a primary astrocyte-disease. The typical pathology of AxD is the accumulation on astrocytes of aggregates called Rosenthal Fiber (RF), the inclusions mainly composed of GFAP and αB-crystallin. Although AxD is initiated by mutation of GFAP, activation of microglia was also observed in the AxD brain. We previously found that the number of microglia increases in the hippocampus of AxD model mice, in which human GFAP with R239H mutation are overexpressed (60TM mice). When microglia were depleted by treatment with PLX5622 (PLX), a CSF-1 receptor antagonist, the AxD pathology worsened, suggesting that microglia should have a protective role against AxD. If so, microglial neuroprotection is expected to be attenuated as the disease progress, and thus, we reasoned if renewal of microglia caused more protection and planned to replace old microglia by an on/off protocol of PLX. By this, microglia were repopulated and they significantly reduced FJB-positive signals, the marker for RF, in 60TM mice, indicating much stronger potential of repopulated microglia against AxD. Hence, microglia play a major role in regulation and suppression of AxD, even though this is a primary astrocyte-disease. Since the pharmacological control of microglia by PLX is safe and simple, we would like to propose an entirely new therapeutic strategy to suppress AxD by microglial interventions. | | 2020/9/12 14:00～14:15 オンデマンドA-2
WD16
脳神経細胞の軸索ミトコンドリアの減少はタンパク質分解機能の低下とユビキチン化タンパク質の蓄積を引き起こす
Depletion of axonal mitochondria disrupts protein degradation pathways and induces accumulation of ubiquitinated proteins in the brain
*真野 叶子1、鈴木 えみ子3,4,1、飯島 浩一5,6、安藤 香奈絵1,2
1. 都立大院 理、2. 都立大 理、3. 遺伝研、4. 総研大院 生命、5. 国立長寿医療研究センター、6. 名市大院 薬
*Kanako Shinno1, Emiko Suzuki3,4,1, Koichi M Iijima5,6, Kanae Ando1,2
1. Grad Sch of Sci, Tokyo Metropolitan Univ., 2. Sch of Sci, Tokyo Metropolitan Univ., 3. NIG, 4. Sch of Life Sci, SOKENDAI, 5. NCGG, 6. Grad Sch of Pharmaceutical Sci, Nagoya City Univ.
Mitochondria are transported actively in the neuronal axon. Defects in axonal transport of mitochondria have been associated with aging and neurodegenerative diseases such as Alzheimer's disease. Abnormal accumulation of proteins in neurons often co-exists with mitochondrial abnormalities, and both of them are thought to contribute to neuronal death, under these disease conditions. However, the role of mitochondria in protein homeostasis is not well understood.
Using Drosophila as a genetic model, here we report that depletion of axonal mitochondria accelerates impairment of proteostasis in the brain during aging. We previously showed that depletion of axonal mitochondria by neuronal knockdown of milton or Miro, adaptor proteins for axonal transport of mitochondria, causes age-dependent neurodegeneration. We found that ubiquitinated proteins were accumulated, and autophagic activity were significantly reduced, in these brains. Ultrastructural analysis detected dense material, which also suggests protein accumulation. These changes were observed in the brain of aged controls, suggesting that the decline in proteostasis during aging was accelerated by depletion of axonal mitohcondria.
To investigate whether the decline in proteostasis in milton knockdown brain is due to ATP insufficiency, we asked whether overall reductions in ATP levels showed similar effects. We found that a hypomorph mutation in a mitochondrial ribosomal protein, which is known to cause an overall decrease in ATP, did not cause either accumulation of ubiquitinated proteins or autophagic defects. These results suggest that accumulation of ubiquitinated proteins observed in the milton knockdown brain is due to mislocation of mitochondria rather than an overall reduction of ATP.
Taken together, our results suggest that the reduction in the axonal distribution of mitochondria contributes to age-associated reduction in proteostasis in the brain, which may contribute to the pathogenesis of neurodegenerative diseases with proteinopathy. | |
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