Pathogenesis role of programmed cell death-1 in Parkinson's disease mouse model

• Project/Area Number: 19K22603
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Juntendo University
• Principal Investigator: Hattori Nobutaka 順天堂大学, 大学院医学研究科, 教授 (80218510)
• Co-Investigator(Kenkyū-buntansha): 佐藤 栄人 順天堂大学, 医学部, 先任准教授 (00445537) ; 波田野 琢 順天堂大学, 大学院医学研究科, 准教授 (60338390) ; 森 聡生 順天堂大学, 医学部, 非常勤助教 (60782878) ; 上野 真一 順天堂大学, 医学部, 特任助教 (40875944)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: パーキンソン病 / Programmed cell death-1 / 制御性T細胞 / α-シヌクレイン（AS) / 腸脳関連 / 腸脳連関 / α-シヌクレイン

Outline of Research at the Start

パーキンソン病（PD）の病態に炎症の関与が示唆されているが、どの様な免疫システムが関与するかは不明な点が多い。しかし、近年α-シヌクレイン(AS)が、腸から迷走神経を介して脳へ伝播する事が報告され、ASの病的な蓄積に腸内細菌叢の変化や全身炎症が関与している可能性が示唆されている。そこで、脳のみならず腸を中心とした全身炎症がPD発症に関連すると仮説を立てた。この仮説を明らかにするために制御性T細胞に関連するprogrammed cell death-1(PD-1)への抗体およびPD-1ノックアウトマウスとPDモデルマウスを用いてASの凝集及びドパミン神経細胞変性と炎症の関連について検討する。

Outline of Final Research Achievements

In PD-1 knockout mice, human α-synuclein (AS) transgenic mice, wild type (WT), and glucocerebrosidase (GBA) gene L444P knock-in mice, there were no significant differences in propagation or aggregation of AS in the brain, shedding of tyrosine hydroxylase positive neurons, or behavioral analysis. On the other hand, inflammatory cytokines tended to increase in the brains of PD-1 knockout mice and GBA L444P knockin mice. Injection of AS seeds into the brains of PD-1 knockout mice did not show any significant change compared to WT mice, and further studies will be conducted in GBA knock-in mice.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病(PD）の原因タンパクとして考えられているα-シヌクレイン(AS)は、全身炎症により凝集が引き起こされることが想定され、免疫チェックポイント分子であるProgrammed cell death-1(PD-1）阻害により全身炎症が惹起し、さらにPDのリスク遺伝子であるグルコセレブロシダーゼ(GBA)遺伝子変異を有することで脳内での炎症は増加する傾向にありAS凝集が促進する可能性がある。

Research Products

• [Journal Article] Homeostatic p62 levels and inclusion body formation in CHCHD2 knockout mice (2021)
  • Author(s): Sato Shigeto、Noda Sachiko、Torii Satoru、Amo Taku、Ikeda Aya、Funayama Manabu、Yamaguchi Junji、Fukuda Takahiro、Kondo Hiromi、Tada Norihiro、Arakawa Satoko、Watanabe Masahiko、Uchiyama Yasuo、Shimizu Shigeomi、Hattori Nobutaka
  • Journal Title: Human Molecular Genetics Volume: 30 Issue: 6 Pages: 443-453
  • DOI: 10.1093/hmg/ddab057
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Seeding Assay Using Cultured Cells (2021)
  • Author(s): Ogata Jun、Takemoto Daisaku、Shimonaka Shotaro、Imai Yuzuru、Hattori Nobutaka
  • Journal Title: Methods Mol Biol. Volume: 2322 Pages: 27-39
  • DOI: 10.1007/978-1-0716-1495-2_3
  • ISBN: 9781071614945, 9781071614952
• [Journal Article] White matter alterations in Parkinson's disease with levodopa-induced dyskinesia (2021)
  • Author(s): Ogawa Takashi、Hatano Taku、Kamagata Koji、Andica Christina、Takeshige-Amano Haruka、Uchida Wataru、Saito Yuya、Shimo Yasushi、Oyama Genko、Umemura Atsushi、Iwamuro Hirokazu、Ito Masanobu、Hori Masaaki、Aoki Shigeki、Hattori Nobutaka
  • Journal Title: Parkinsonism & Related Disorders Volume: 90 Pages: 8-14
  • DOI: 10.1016/j.parkreldis.2021.07.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-invasive diagnostic tool for Parkinson’s disease by sebum RNA profile with machine learning (2021)
  • Author(s): Uehara Yuya、Ueno Shin-Ichi、Amano-Takeshige Haruka、Suzuki Shuji、Imamichi Yoko、Fujimaki Motoki、Ota Noriyasu、Murase Takatoshi、Inoue Takayoshi、Saiki Shinji、Hattori Nobutaka
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 18550-18550
  • DOI: 10.1038/s41598-021-98423-9
  • Peer Reviewed / Open Access
• [Journal Article] Sato S, Noda S, Hattori N. (2020)
  • Author(s): Pathogenic insights to Parkin-linked model mice.
  • Journal Title: Neurosci Res. Volume: 159 Pages: 47-51
  • DOI: 10.1016/j.neures.2020.03.014
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice. (2020)
  • Author(s): Noda S, Sato S, Fukuda T, Tada N, Uchiyama Y, Tanaka K, Hattori N.
  • Journal Title: Neurobiol Dis. Volume: 136 Pages: 104717-104717
  • DOI: 10.1016/j.nbd.2019.104717
  • Peer Reviewed / Open Access
• [Journal Article] Ueno SI, Oyama G, Kanai K, Hatano T, Shimo Y, Hattori N. A Retrospective Imaging Evaluation of Presynaptic Dopaminergic Degeneration in Multiple System Atrophy with Levodopa Induced Dyskinesia. (2020)
  • Author(s): Ueno SI, Oyama G, Kanai K, Hatano T, Shimo Y, Hattori N
  • Journal Title: Tremor Other Hyperkinet Mov (N Y). Volume: 10 Issue: 0 Pages: 6-6
  • DOI: 10.5334/tohm.58
  • Peer Reviewed
• [Journal Article] Lipids: Key Players That Modulate -Synuclein Toxicity and Neurodegeneration in Parkinson’s Disease (2020)
  • Author(s): Akio Mori, Yuzuru Imai, Nobutaka Hattori
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 9 Pages: 9-9
  • DOI: 10.3390/ijms21093301
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease (2020)
  • Author(s): Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa KI, Okuzumi A, Noda S, Sato S, Satake W, Toda T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T, Yoshino H, Nishioka K, Hattori T, Mizutani Y, Mutoh T, Yokochi F, et al.
  • Journal Title: Brain Volume: 143 Issue: 4 Pages: 1190-1205
  • DOI: 10.1093/brain/awaa064
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aging-related motor function and dopaminergic neuronal loss in C57BL/6 mice. (2020)
  • Author(s): Noda S, Sato S, Fukuda T, Tada N, Hattori N.
  • Journal Title: Mol Brain. Volume: 13 Issue: 1 Pages: 46-46
  • DOI: 10.1186/s13041-020-00585-6
  • Peer Reviewed / Open Access
• [Journal Article] A metabolic profile of polyamines in parkinson disease: A promising biomarker (2019)
  • Author(s): Saiki Shinji、Sasazawa Yukiko、Fujimaki Motoki、Kamagata Koji、Kaga Naoko、Taka Hikari、Li Yuanzhe、Souma Sanae、Hatano Taku、Imamichi Yoko、Furuya Norihiko、Mori Akio、Oji Yutaka、Ueno Shin‐Ichi、Nojiri Shuko、Miura Yoshiki、Ueno Takashi、Funayama Manabu、Aoki Shigeki、Hattori Nobutaka
  • Journal Title: Annals of Neurology Volume: 86 Issue: 2 Pages: 251-263
  • DOI: 10.1002/ana.25516
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomics‐based identification of metabolic alterations in PARK2 (2019)
  • Author(s): Okuzumi Ayami、Hatano Taku、Ueno Shin‐Ichi、Ogawa Takashi、Saiki Shinji、Mori Akio、Koinuma Takahiro、Oji Yutaka、Ishikawa Kei‐Ichi、Fujimaki Motoki、Sato Shigeto、Ramamoorthy Sivapriya、Mohney Robert P.、Hattori Nobutaka
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 6 Issue: 3 Pages: 525-536
  • DOI: 10.1002/acn3.724
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Plasma metabolite biomarkers for multiple system atrophy and progressive supranuclear palsy (2019)
  • Author(s): Mori Akio、Ishikawa Kei-Ichi、Saiki Shinji、Hatano Taku、Oji Yutaka、Okuzumi Ayami、Fujimaki Motoki、Koinuma Takahiro、Ueno Shin-Ichi、Imamichi Yoko、Hattori Nobutaka
  • Journal Title: PLOS ONE Volume: 14 Issue: 9 Pages: e0223113-e0223113
  • DOI: 10.1371/journal.pone.0223113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Parkinson's disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling. (2019)
  • Author(s): Mori A, Hatano T, Inoshita T, Shiba-Fukushima K, Koinuma T, Meng H, Kubo SI, Spratt S, Cui C, Yamashita C, Miki Y, Yamamoto K, Hirabayashi T, Murakami M, Takahashi Y, Shindou H, Nonaka T, Hasegawa M, Okuzumi A, Imai Y, Hattori N.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116(41) Issue: 41 Pages: 20689-20699
  • DOI: 10.1073/pnas.1902958116
  • NAID: 120007132272
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 脂質代謝異常とαシヌクレイン凝集Selective vulnerability of alpha-synuclein-related neurodegeneration -beyond proteinopathy and propagation（シンポジウム） (2021)
  • Author(s): 波田野 琢、王子 悠、森 聡生、服部信孝
  • Organizer: 第62回日本神経学会学術大会
• [Presentation] Structure and propagation of aggregated proteins, Neuroscience Frontier Symposium(シンポジウム）) (2021)
  • Author(s): 奥住文美、波田野 琢、貫名信行、服部信孝
  • Organizer: 第62回日本神経学会学術大会
• [Presentation] パーキンソン病とPhysical Activity Scale in the Elderlyとの関連についての検討（ポスター） (2021)
  • Author(s): 若盛 亮、王子 悠、小川 崇、竹重遥香、上野真一、波田野 琢、服部信孝
  • Organizer: 第62回日本神経学会学術大会、2021年5月20日、国立京都国際会館、京都
• [Presentation] Loss of CHCHD2 causes inclusion body formation and dopaminergic neuronal loss in aged mice（口演） (2021)
  • Author(s): 佐藤栄人、野田幸子、天羽 拓、池田 彩、舩山 学、清水重臣、服部信孝
  • Organizer: 第62回日本神経学会学術大会
• [Presentation] Loss of CHCHD2 affects mitochondrial structure and dopaminergic neuronal loss in aged mice (2020)
  • Author(s): 佐藤栄人、野田幸子、舩山 学、服部信孝
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] ATP13A2/PARK9 protects brains from a-synuclein propagation (2020)
  • Author(s): 常深泰司、石黒雄太、鎧坂朝子、奥住文美、貫名信行、服部信孝
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Development of PD mouse models with alpha-synuclein injection for assessment of chemical efficacy (2020)
  • Author(s): 石丸友博、斉木臣二、奥住文美、笹澤有紀子、福原武志、井本正哉、服部信孝
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] White matter alterations in Multiple System Atrophy-parkinsonian variant (2020)
  • Author(s): 小川 崇、波田野 琢、竹重遙香、鎌形康司、Christina Andica、内田 航、濃沼崇博、中村亮太、岩室宏一、大山彦光、下 泰司、梅村 淳、伊藤賢伸、青木茂樹、服部信孝
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] パーキンソン病・PARK2患者におけるバイオマーカーとしての酸化型アルブミン. (2019)
  • Author(s): 上野真一, 波田野琢, 奥住文美, 斉木臣二, 王子悠, 森聡生, 濃沼崇博, 藤巻基紀, 安川惠子, 矢冨裕, 池田均, 服部信孝.
  • Organizer: 第13回パーキンソン病・運動障害学会コングレス
• [Presentation] Serum non-mercaptalbumin as a potential biomarker in Parkinson’s disease and related disorders (2019)
  • Author(s): Ueno SI, Hatano T, Okuzumi A, Saiki S, Oji Y, Mori A, Koinuma T, Fujimaki M, Takeshige-Amano H, Yasukawa K, Yatomi Y, Ikeda H, Hattori N.
  • Organizer: 23rd International Congress of Parkinson’s Disease and Movement Disorders. Sep 22-26, Nice, France.
  • Int'l Joint Research
• [Presentation] Synaptic dysfunction in a Drosophila model of PARK14 (2019)
  • Author(s): Hatano T, Mori A, Inoshita T, Fukushima-Shiba K, Koinuma T, Yamashita C, Imai Y, Hattori N.
  • Organizer: 23rd International Congress of Parkinson’s Disease and Movement Disorders. Sep 22-26, Nice, France.
  • Int'l Joint Research
• [Presentation] The evaluation of exosomes as a biomarker of Parkinson’s disease (2019)
  • Author(s): Ishiguro Y, Tsunemi T, Yoroizaka A, Hattori N.
  • Organizer: 23rd International Congress of Parkinson’s Disease and Movement Disorders. Sep 22-26, Nice, France.
• [Book] 順天堂大脳神経内科ではこうしている 最新 パーキンソン病診療【電子版付】 (2021)
  • Author(s): 服部信孝
  • Total Pages: 224
  • Publisher: 日本医事新報社
  • ISBN: 9784784949502
• [Book] ウルトラ図解 パーキンソン病 (2020)
  • Author(s): 服部 信孝
  • Total Pages: 160
  • Publisher: 株式会社法研
  • ISBN: 9784865136128
• [Book] 治療薬ハンドブック2020 (2020)
  • Author(s): 髙久 史麿、堀 正二、菅野 健太郎、門脇 孝、乾 賢一、林 昌洋、服部信孝（パーキンソン病薬）
  • Total Pages: 1586
  • Publisher: じほう
  • ISBN: 9784840752282
• [Book] 大脳基底核の変性疾患、神経疾患、6 神経変性疾患、内科学書 Vol. 6 改訂第9版、神経疾患 (2019)
  • Author(s): 服部信孝
  • Total Pages: 659
  • Publisher: 株式会社 中山書店
  • ISBN: 9784521747491
• [Funded Workshop] The 19th “Takamatsu” International Symposium for PD & MD ((IPDST) (2020)