一般口演
神経変性疾患 1
Neurodegenerative Disorders 1
座長：池中 健介（大阪大学大学院医学系研究科） |
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| 2022年7月2日 10:00～10:15 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04m2-01
リン脂質Aはαシヌクレインと結合しパーキンソン病様の構造多型を持つ凝集体形成を促進する
Phospholipid A triggers the formation of Parkinson’s disease-like fibrils of alpha-synuclein
*池中 建介(1)、Choong Chi-Jin(1)、Cesar Aguirre(1)、角田 渓太(1)、望月 秀樹(1)
1. 大阪大学大学院医学系研究科
*Kensuke Ikenaka Ikenaka(1), Choong Chi-Jin(1), Cesar Aguirre(1), Keita Kakuda(1), Hideki Mochizuki(1)
1. Osaka University Graduate school of Medicine
Keyword: Parkinson's disease, alpha synuclein, phospholipid, neurodegeneragtive disease
An increasing number of evidence has shown that the interaction between lipid membranes plays a key role in initiating the pathological aggregation of alpha-synuclein (αSyn). Glucosylceramide accumulation has been implicated in the toxic conversion of αSyn in Parkinson’s disease (PD) with a heterozygous mutation of glucocerebrosidase, however, the involvement of other lipids in idiopathic PD remains largely unknown. In this study, we performed a membrane-based screening of 28 biologically important lipids which are present in the cellular membranes and found that phospholipid A shows the strongest interaction with αSyn. Interestingly, in vitro aggregation assay revealed that phospholipid A not only accelerates the aggregation of αSyn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brain of PD patients. Treatment of cultured cells with phospholipid A itself or with phospholipid A phosphatase inhibitor, induced intracellular formation of αSyn inclusions. Loss-of-function mutation of synaptojanin1, an enzyme that dephosphorylates the D-5 position phosphate from phospholipid A, causes familial PD (PARK20) and we showed that loss of synaptojanin1 triggers the accumulation of αSyn in a cultured cell model and in a Caenorhabditis elegans model. Notably, immunohistochemical analysis revealed increased immunoreactivity of phospholipid A and its colocalization with αSyn in the postmortem brains of PD patients. Taken together, these findings indicate that phospholipid A dysregulation promotes pathological aggregation of αSyn and increases the risk of developing Parkinson’s disease. | | 2022年7月2日 10:15～10:30 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04m2-02
脂肪酸結合タンパク質5/7は多発性硬化症マウスのオリゴデンドロサイト障害に関与する
Fatty acid-binding proteins 5/7 mediate the oligodendrocyte injury in a multiple sclerosis mouse model
*福永 浩司(1,2)、程 岸(1)、川畑 伊知郎(1)
1. 東北大学大学院薬学研究科、2. BRIファーマ（株）
*Kohji Fukunaga(1,2), Cheng An(1), Ichiro Kawahata(1)
1. Tohoku University Grad Sch Pharm Sci, Sendai, Japan, 2. BRI Pharma Inc.
Keyword: MULTIPLE SYSTEM ATROPHY, FABP5, FABP7, OLIGODENDROCYTE
Background: Multiple sclerosis (MS) is an autoimmune disease characterized by the demyelination of mature oligodendrocytes in the central nervous system. Recently, several studies have indicated the vital roles of fatty acid-binding proteins (FABPs) 5 and 7 in regulating the immune response.
Methods: We assessed a novel FABP5/FABP7 inhibitor, FABP ligand 6 (MF 6), as a potential therapeutic for MS therapy. In vivo, we established MOG35-55-administered experimental autoimmune encephalomyelitis (EAE) mice as an MS mouse model, followed by prophylactic and symptomatic treatment with MF 6. The therapeutic effect of MF 6 was determined using behavioral and biochemical analyses. In vitro, MF 6 effects on astrocytes and oligodendrocytes were examined using both astrocyte primary culture and KG-1C cell lines.
Results: Prophylactic and symptomatic MF 6 therapy reduced myelin loss and clinical EAE symptoms. Furthermore, oxidative stress levels and GFAP-positive and ionised calcium-binding adaptor protein-1(Iba-1)-positive cells were reduced in the spinal cord of MF 6-treated mice. In addition, MF 6 attenuated lipopolysaccharide- stimulated interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) accumulation in primary astrocyte culture. Moreover, MF 6 indicated a powerful protective function for the mitochondria in the oligodendrocytes of EAE mice via FABP5 inhibition. Conclusion: MF 6 is a potent inhibitor of FABP5 and FABP7; targeted inhibition of IL-1β and TNFα may confer potential therapeutic effects in MS via immune inhibition and oligodendrocyte protection.
Funding: This work was supported by the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development (AMED) (JP20dm0107071). | | 2022年7月2日 10:30～10:45 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04m2-03
パーキンソン病に着目したレム睡眠行動障害のメカニズムの解明
Analysis of the mechanism of REM sleep focusing on behavior disorders associated with Parkinson’s disease
*金子 杏美(1,2)、安垣 進之助(1,3)、早川 英規(4)、池中 建介(4)、Aguirre Cesar(4)、柳沢 正史(1)、馬場 孝輔(4,5)、望月 秀樹(4)、林 悠(1,6)
1. 筑波大学国際統合睡眠医科学研究機構、2. 筑波大学グローバル教育院ヒューマニクス学位プログラム、3. 筑波大学大学院人間総合科学研究科生命システム医学専攻、4. 大阪大学大学院医学系研究科神経内科学、5. 富山大学学術研究部医学系脳神経内科、6. 京都大学大学院医学研究科人間健康科学系専攻
*Ami Kaneko(1,2), Shinnosuke Yasugaki(1,3), Hideki Hayakawa(4), Kensuke Ikenaka(4), Cesar Aguirre(4), Masashi Yanagisawa(1), Kousuke Baba(4,5), Hideki Mochizuki(4), Yu Hayashi(1,6)
1. WPI-IIIS, Univ of Tsukuba, 2. Ph. D. Prog in Humanics, SIGMA, Univ of Tsukuba, 3. Doc Prog in Biomed Sci, Grad Sch of Comprehensive Human Sci, Univ of Tsukuba, 4. Dept of Neurology, Grad Sch of Medicine, Osaka Univ, 5. Dept of Neurology, Faculty of Medicine, Acad Res Division, Univ of Toyama, 6. Dept of Human Health Sci, Grad Sch of Medicine, Kyoto Univ
Keyword: REM sleep behavior disorder, Parkinson's disease, α-synuclein, Synucleinopathy
During rapid eye movement (REM) sleep, the cerebral cortex becomes activated and produces vivid dreams. Yet, it normally does not lead to motor output owing to expression of loss of muscle tone (muscle atonia). However, patients with REM sleep behavior disorder (RBD) exhibit impaired muscle atonia during REM sleep and frequently act out of their dreams. For example, the patients talk loudly or exhibit violent movements such as hitting and kicking, which may injure their bed partner. Moreover, patients often wake up following such movements, which can lead to reduced sleep quality and excessive sleepiness or fatigue during the daytime.
A majority of RBD patients co-suffer from synucleinopathies including Parkinson’s disease and dementia with Lewy bodies or eventually develop these diseases within 10-14 years. Thus, RBD is considered as a prodromal of synucleinopathies. In synucleinopathies, α-synuclein accumulates and causes nerve cell death, which leads to motor symptoms such as tremor, bradykinesia, and rigidity as well as non-motor symptoms including sleep disturbances, cognitive impairments, hallucinations and depression.
Here, we aimed to understand the mechanisms underlying the link between RBD and Parkinson’s disease, and establish an RBD mouse model for future development of effective treatment for RBD. A rare G51D α-synuclein mutation is observed in familial Parkinson’s disease, and it leads to the production of toxic α-synuclein fibrils and rapid progression of Parkinson’s disease.
We produced and injected G51D α-synuclein fibrils into the brainstem pontine tegmental area in mice, and examined the effects on muscle atonia during REM sleep, behavior and motor symptoms across several months. We expect that this study will provide important insight to how RBD develops at the early stages of Parkinson’s disease. | | 2022年7月2日 10:45～11:00 沖縄コンベンションセンター 会議場B5～7 第4会場
3O04m2-04
レビー小体病の新規発症機序を標的としたαシヌクレイノパチーの中分子治療薬開発
Impact of fatty acid-binding protein and dopamine receptor in α-synuclein propagation and development of disease-modifying drug for α-synucleinopathy
*川畑 伊知郎(1)、福永 浩司(1)
1. 東北大学大学院薬学研究科
*Ichiro Kawahata(1), Kohji Fukunaga(1)
1. Grad Sch Pharm Sci, Tohoku Univ, Sendai, Japan
Keyword: α-synucleinopathy, fatty acid-binding protein, dopamine D2 receptor, Lewy body disease
α-Synuclein is a protein consisting of 140 amino acid residues that accumulates in dopaminergic nerves and forms aggregates in Parkinson's disease. In order for α-synuclein to accumulate in neurons, the process of protein propagation and cellular uptake is essential. We have recently found that the fatty acid-binding protein FABP3 is essential for α-synuclein uptake in dopaminergic neurons. FABP3 is expressed on dopaminergic neurons in the central nervous system and binds to dopamine D2 long type (D2L) receptors. D2L receptors are known to be abundantly localized in cell membranes, especially in caveolae structures. Therefore, the aim of this study was to elucidate the physiological significance of dopamine D2L receptors and FABP3 in the uptake process of α-synuclein. To analyze the uptake ability of ATTO fluorescence-conjugated α-synuclein monomers and fibrils, we employed mesencephalic neurons derived from dopamine D2L-/-, dopamine D2 receptor null (D2 null), FABP3-/-, and wild-type C57BL6 mice. We also prepared various peptides to block α-synuclein uptake and recover neuronal homeostasis. Immunocytochemical analysis showed that D2L receptor and FABP3 co-localized. In addition, α-synuclein and D2L receptors taken up into the cells were highly co-localized. In contrast, tyrosine hydroxylase (TH)-positive cells in D2L knockout or D2 null knockout showed no uptake of α-synuclein monomers or fibrils. Furthermore, inhibition of caveolae formation by dynamin inhibitors or knockdown of caveolin-1 reduced α-synuclein uptake. The C-terminal deletion of α-synuclein abolished its uptake by dopaminergic neurons. Furthermore, we found that the uptake of α-synuclein could be inhibited by treatment with the C-terminal peptide of α-synuclein. The peptide drug prevented the formation of the α-synuclein-FABP3 complex and restored the multimers to monomer form. The therapy also recovered the learning and memory function in the α-synucleinopathy model mice in vivo. It was suggested that dopamine D2L receptors with caveolae formation and FABP3 are essential for α-synuclein uptake in dopaminergic neurons. In addition, the potential of medium-molecule therapeutics targeting the C-terminal of α-synuclein has been demonstrated, which is expected to be a novel pathogenic mechanism and drug target for synucleinopathies including Parkinson's disease and dementia with Lewy bodies. | |
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