Exploring inflammasome-mediated neuroimmune regulation in Parkinson's disease and multiple system atrophy

• Project/Area Number: 19K16277
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Kyoto University
• Principal Investigator: Takashi Ayaki 京都大学, 医学研究科, 助教 (60749555)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: α-シヌクレイン / ミクログリア / インフラマソーム / NLRP3 / IL1β / STING / 自然免疫

Outline of Research at the Start

パーキンソン病や多系統萎縮症などのα-シヌクレイノパチーで、ミクログリアのインフラマソームの活動を介したIL1β分泌が亢進していることを確認し、疾患モデル細胞において、神経細胞死の制御が可能であることを明らかにすることである。
具体的には、①疾患の剖検脳を用いて、インフラマソーム関連タンパク質の免疫染色による神経組織学的検討、ウェスタンブロットやELISA法による定量評価する②患者の髄液内のIL1βの量をELISA法で測定し上昇を確認する③ミクログリア及び神経細胞培養細胞を用いて、α-シヌクレインに対する応答を解析し、インフラマソームの活動の抑制によって神経細胞死阻害可能であることを確認する。

Outline of Final Research Achievements

In 2019, we reported behavioral abnormalities in mice with synuclein mutations compared with analysis results in human tissues. In 2020, I reported that inflammation and intracellular inclusion bodies were observed in the muscle pathology of Nakajo Nishimura disease caused by proteasome mutation.
In 2021, we will examine the STING pathway, which is one of the innate immunity, as well as the inflammasome, with regard to neuroinflammatory signals. We reported an increase in STING-related protein-positive microglia and measured interleukin levels in patients' cerebrospinal fluid. Experimental results were reported for the STING pathway with Inoue et al.

Academic Significance and Societal Importance of the Research Achievements

多系統萎縮症、パーキンソン病でのシヌクレイノパチーで、自然免疫系の反応を明らかにした。また他の神経変性疾患（中条西村症候群）での、炎症系シグナルの反応を明らかにした。仮説として、変性疾患における変性タンパクに対する免疫応答機序が想定された。また、社会的には、変性疾患（特にアルツハイマー病）に対するワクチン治療が始まっており、変性疾患に対する免疫応答は治療探求にも重要である。今回の研究結果は、変性疾患に対する免疫応答は治療探求に示唆を与え、貢献する結果であると考えた。

Research Products

• [Journal Article] White matter edematous change with moderate vascular lesions in pretreated acute stage of leukoencephalopathy with cerebral amyloid angiopathy (2022)
  • Author(s): Yasuda Ken、Ayaki Takashi、Li Fangzhou、Kuwata Yasuhiro、Maki Takakuni、Sainouchi Makoto、Moriyoshi Koki、Nakamura Michikazu、Takahashi Ryosuke
  • Journal Title: Neuropathology Volume: 42 Issue: 2 Pages: 134-140
  • DOI: 10.1111/neup.12782
  • Peer Reviewed
• [Journal Article] Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro (2022)
  • Author(s): Asada-Utsugi Megumi、Uemura Kengo、Ayaki Takashi、T. Uemura Maiko、Minamiyama Sumio、Hikiami Ryota、Morimura Toshifumi、Shodai Akemi、Ueki Takatoshi、Takahashi Ryosuke、Kinoshita Ayae、Urushitani Makoto
  • Journal Title: Communications Biology Volume: 5 Issue: 1 Pages: 00-00
  • DOI: 10.1038/s42003-022-03312-0
  • Peer Reviewed / Open Access
• [Journal Article] Conformational change of RNA-helicase DHX30 by ALS/FTD-linked FUS induces mitochondrial dysfunction and cytosolic aggregates (2022)
  • Author(s): Hikiami R, Morimura T, Ayaki T, Tsukiyama T, Morimura N, Kusui M, Wada H, Minamiyama S, Shodai A, Asada-Utsugi M, Muramatsu SI, Ueki T, Takahashi R, Urushitani M.
  • Journal Title: Scxeintific Reports Volume: 12 Issue: 1 Pages: 16030-16046
  • DOI: 10.1038/s41598-022-20405-2
  • Peer Reviewed / Open Access
• [Journal Article] DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers. (2022)
  • Author(s): 1.Jin M., Matsumoto S., Ayaki T., Yamakado H., Taguchi T., Togawa N., Konno A., Hirai H., Nakajima H., Komai S., Ishida R., Chiba S., Takahashi R., Takao T. and Hirotsune S.
  • Journal Title: Nature Communications Volume: 13(1):6880 Issue: 1 Pages: 6880-6880
  • DOI: 10.1038/s41467-022-34555-4
  • Peer Reviewed / Open Access
• [Journal Article] Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial (2022)
  • Author(s): Imamura K、Izumi Y、Nagai M、Nishiyama K、Watanabe Y、Hanajima R、Egawa N、Ayaki T、Oki R、Fujita K、Uozumi R、Morinaga A、Hirohashi T、Fujii Y、Yamamoto T、Tatebe H、Tokuda T、Takahashi N、Morita S、Takahashi R、Inoue H
  • Journal Title: eClinicalMedicine Volume: 53 Pages: 101707-101707
  • DOI: 10.1016/j.eclinm.2022.101707
  • Peer Reviewed / Open Access
• [Journal Article] An autopsy case of adult‐onset neuronal intranuclear inclusion disease with perivascular preservation in cerebral white matter (2022)
  • Author(s): Yoshii Daisuke、Ayaki Takashi、Wada Takafumi、Ozaki Akihiko、Yamamoto Toru、Miyagi Yoshimi、Senzaki Hideto、Takahashi Ryosuke
  • Journal Title: Neuropathology Volume: 42 Issue: 1 Pages: 66-73
  • DOI: 10.1111/neup.12778
• [Journal Article] Insertable inductively coupled volumetric coils for MR microscopy in a human 7T MR system (2021)
  • Author(s): Okada Tomohisa、Handa Shinya、Ding Bill、Urayama Shin‐ichi、Fujimoto Koji、Shima Atsushi、Yoshii Daisuke、Ayaki Takashi、Sawamoto Nobukatsu、Takahashi Ryosuke、Onoe Hirotaka、Isa Tadashi、Petropoulos Labros
  • Journal Title: Magnetic Resonance in Medicine Volume: 87 Issue: 3 Pages: 1613-1620
  • DOI: 10.1002/mrm.29062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The stimulator of interferon genes (STING) pathway is upregulated in striatal astrocytes of patients with multiple system atrophy (2021)
  • Author(s): Yutaka Inoue, Takashi Ayaki, Tomoyuki Ishimoto, Hodaka Yamakado, Takakuni Maki , Shuichi Matsuzawa, Nobukatsu Sawamoto, Ryosuke Takahashi
  • Journal Title: Neurosci Lett . Volume: 757 Pages: 135972-135972
• [Journal Article] Monoclonal gammopathy of renal significance (MGRS)-related AL amyloidosis complicated by amyloid myopathy: a case report (2021)
  • Author(s): Ono Erina、Ishii Akira、Higashi Yoshiaki、Koita Natsuko、Ayaki Takashi、Tanigaki Katsuya、Takayanagi Shunsuke、Kondo Naoya、Sakai Kaoru、Endo Shuichiro、Yokoi Hideki、Matsubara Takeshi、Minamiguchi Sachiko、Nishino Ichizo、Takahashi Ryosuke、Yanagita Motoko
  • Journal Title: BMC Nephrology Volume: 22 Issue: 1 Pages: 74-74
  • DOI: 10.1186/s12882-021-02272-7
• [Journal Article] Optineurin defects cause TDP43-pathology with autophagic vacuolar formation. (2021)
  • Author(s): Kurashige T, Kuramochi M, Ohsawa R, Yamashita Y, Shioi G, Morino H, Kamada M, Ayaki T, Ito H, Sotomaru Y, Maruyama H, Kawakami H.
  • Journal Title: Neurobiol Dis Volume: 148 Pages: 105215-105215
• [Journal Article] Optineurin defects cause TDP43-pathology with autophagic vacuolar formation (2021)
  • Author(s): Kurashige Takashi、Kuramochi Masahito、Ohsawa Ryosuke、Yamashita Yui、Shioi Go、Morino Hiroyuki、Kamada Masaki、Ayaki Takashi、Ito Hidefumi、Sotomaru Yusuke、Maruyama Hirofumi、Kawakami Hideshi
  • Journal Title: Neurobiology of Disease Volume: 148 Pages: 105215-105215
  • DOI: 10.1016/j.nbd.2020.105215
  • Peer Reviewed / Open Access
• [Journal Article] Japanese Familial Cases of Frontotemporal Dementia and Parkinsonism with N279K Tau Gene Mutation (2020)
  • Author(s): Oka Yuwa、Saiki Hidemoto、Hashimoto Yasumasa、Terada Yuta、Nakamura Takashi、Ayaki Takashi、Orimo Satoshi、Matsumoto Sadayuki
  • Journal Title: Movement Disorders Clinical Practice Volume: 8 Issue: 1 Pages: 126-132
  • DOI: 10.1002/mdc3.13100
• [Journal Article] Accumulation of HAX-1 and PARL in brainstem- and cortical-type Lewy bodies in Parkinson's disease and dementia with Lewy bodies (2020)
  • Author(s): Kawamoto Yasuhiro、Ayaki Takashi、Urushitani Makoto、Ito Hidefumi、Takahashi Ryosuke
  • Journal Title: Journal of the Neurological Sciences Volume: 415 Pages: 116928-116928
  • DOI: 10.1016/j.jns.2020.116928
  • Peer Reviewed
• [Journal Article] BCAS1-positive immature oligodendrocytes are affected by the α-synuclein-induced pathology of multiple system atrophy (2020)
  • Author(s): Kaji S, Maki T, Ueda J, Ishimoto T, Inoue Y, Yasuda K, Sawamura M, Hikawa R, Ayaki T, Yamakado H, Takahashi R
  • Journal Title: Acta Neuropathol Commun. 2020 Jul 29;8(1):120. doi: 10.1186/s40478-020-00997-4. PMID: 32727582; PMCID: PMC7391509 Volume: 8 Issue: 1 Pages: 120-120
  • DOI: 10.1186/s40478-020-00997-4
  • Peer Reviewed / Open Access
• [Journal Article] Myositis with sarcoplasmic inclusions in Nakajo‐Nishimura syndrome: a genetic inflammatory myopathy (2020)
  • Author(s): Takashi Ayaki、Kenya Murata、Kanazawa Nobuo、Akinori Uruha、Koichiro Ohmura、Kazuma Sugie、Shimpei Kasagi、Fangzhou Li、Megumi Mori、Nakajima Ran、Sasai Tsuneo、Nishino Ichizo、Satoshi Ueno、Makoto Urushitani、Fukumi Furukawa、Ito Hidefumi、Takahashi Ryosuke
  • Journal Title: Neuropathology and Applied Neurobiology Volume: 00 Issue: 6 Pages: 00-00
  • DOI: 10.1111/nan.12614
  • Peer Reviewed
• [Journal Article] a-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia:a prodromal Parkinson’s disease model (2020)
  • Author(s): Taguchi T, Ikuno M, Hondo M, Parajuli LK, Taguchi K, Ueda J, Sawamura M, Okuda S, Nakanishi E, Hara J, Uemura N, Hatanaka Y, Ayaki T, Matsuzawa S, Tanaka M, El-Agnaf OMA, Koike M, Yanagisawa M, Uemura MT, Yamakado H, Takahashi R
  • Journal Title: BRAIN Volume: 143 Issue: 1 Pages: 249-265
  • DOI: 10.1093/brain/awz380
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recurrent Epstein-Barr Virus-positive (EBV+) Primary Central Nervous System Lymphoma (PCNSL) in a Patient with Clinical Features of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) (2019)
  • Author(s): Nagano Masahiro、Ayaki Takashi、Koita Natsuko、Kitano Toshiyuki、Nishikori Momoko、Goda Naoki、Minamiguchi Sachiko、Ikeda Akio、Takaori-Kondo Akifumi、Takahashi Ryosuke
  • Journal Title: Internal Medicine Volume: 58 Issue: 6 Pages: 849-854
  • DOI: 10.2169/internalmedicine.1246-18
  • NAID: 130007611374
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-03-15
  • Peer Reviewed / Open Access
• [Journal Article] Linear Polyubiquitin Chain Modification of TDP-43-Positive Neuronal Cytoplasmic Inclusions in Amyotrophic Lateral Sclerosis (2019)
  • Author(s): Nakayama Yoshiaki、Tsuji Kazumi、Ayaki Takashi、Mori Megumi、Tokunaga Fuminori、Ito Hidefumi
  • Journal Title: Journal of Neuropathology & Experimental Neurology Volume: 79 Issue: 3 Pages: 256-265
  • DOI: 10.1093/jnen/nlz135
  • Peer Reviewed
• [Journal Article] Induced pluripotent stem cell?based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients (2019)
  • Author(s): Imamura Keiko、Izumi Yuishin、Banno Haruhiko、Uozumi Ryuji、Morita Satoshi、Egawa Naohiro、Ayaki Takashi、、et al.
  • Journal Title: BMJ Open Volume: 9 Issue: 12 Pages: e033131-e033131
  • DOI: 10.1136/bmjopen-2019-033131
  • NAID: 120006826750
  • Peer Reviewed / Open Access
• [Journal Article] Two cases of delayed perforating artery infarction adjacent to intracranial hemorrhage (2019)
  • Author(s): Yasuda Ken、Maki Takakuni、Kimura Kimitoshi、Ayaki Takashi、Sawamoto Nobukatsu、Murase Nagako、Ohtani Ryo、Takahashi Ryosuke、Nakamura Michikazu
  • Journal Title: eNeurologicalSci Volume: 17 Pages: 100209-100209
  • DOI: 10.1016/j.ensci.2019.100209
• [Journal Article] Role of Perivascular Oligodendrocyte Precursor Cells in Angiogenesis After Brain Ischemia (2019)
  • Author(s): Kishida Natsue、Maki Takakuni、Takagi Yasushi、Yasuda Ken、Kinoshita Hisanori、Ayaki Takashi、Noro Takayuki、Kinoshita Yusuke、Ono Yuichi、Kataoka Hiroharu、Yoshida Kazumichi、Lo Eng H.、Arai Ken、Miyamoto Susumu、Takahashi Ryosuke
  • Journal Title: Journal of the American Heart Association Volume: 8 Issue: 9
  • DOI: 10.1161/jaha.118.011824
  • NAID: 120006980544
  • Peer Reviewed / Open Access
• [Journal Article] Chronic cerebral hypoperfusion upregulates leptin receptor expression in astrocytes and tau phosphorylation in tau transgenic mice. (2019)
  • Author(s): Shimada T, Shindo A, Matsuyama H, Yata K, Niwa A, Sasaki R, Ayaki T, Maki T, Wakita H, Tomimoto H.
  • Journal Title: Neuroscience Letters Volume: 704 Pages: 133-140
  • DOI: 10.1016/j.neulet.2019.04.009
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylated NF-κB subunit p65 aggregates in granulovacuolar degeneration and neurites in neurodegenerative diseases with tauopathy (2019)
  • Author(s): Yamaguchi Yuko、Ayaki Takashi、Li Fangzhou、Tsujimura Atsushi、Kamada Masaki、Ito Hidefumi、Maki Takakuni、Sawamoto Nobukatsu、Urushitani Makoto、Takahashi Ryosuke
  • Journal Title: Neuroscience Letters Volume: 704 Pages: 229-235
  • DOI: 10.1016/j.neulet.2019.03.036
  • Peer Reviewed
• [Journal Article] An autopsy case after endovascular thrombectomy for cardioembolic stroke due to nonbacterial thrombotic endocarditis (2019)
  • Author(s): Yasuda K, Ayaki T, Kawabata Y, Murase N, Ohtani R, Nakamura M.
  • Journal Title: Rinsho Shinkeigaku Volume: 59 Issue: 4 Pages: 195-199
  • DOI: 10.5692/clinicalneurol.cn-001252
  • NAID: 130007636894
  • ISSN: 0009-918X, 1882-0654
  • Peer Reviewed
• [Journal Article] Identification of linear polyubiquitin chain immunoreactivity in tau pathology of Alzheimer’s disease (2019)
  • Author(s): Nakayama Yoshiaki、Sakamoto Shinji、Tsuji Kazumi、Ayaki Takashi、Tokunaga Fuminori、Ito Hidefumi
  • Journal Title: Neuroscience Letters Volume: 703 Pages: 53-57
  • DOI: 10.1016/j.neulet.2019.03.017
  • Peer Reviewed