Analysis of propagation risk factors for food-derived alpha-Synuclein seeds

• Project/Area Number: 20K21531
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: Juntendo University
• Principal Investigator: Imai Yuzuru 順天堂大学, 大学院医学研究科, 先任准教授 (30321730)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2021: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2020: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: α-Synuclein / パーキンソン病 / ショウジョウバエ / 炎症 / 消化管 / プリオン病 / セロトニン神経 / タンパク質凝集 / 神経変性 / alpha-synuclein / Drosophila / 伝搬

Outline of Research at the Start

狂牛病（BSE）は感染したウシ肉骨粉を食べただけで発症するウシのプリオン病である。プリオン病は、病因構造のプリオンタンパク質が正常型の内在性プリオンタンパク質を次々に病因型に構造変換していくことにより発症する。パーキンソン病は、α-Synucleinの凝集が神経回路を伝搬して広がる「プリオン病」の一種であることが明らかになってきた。本研究では、消化管経由で取り込まれる食肉由来の病因性α-Synucleinが、α-Synuclein凝集の起源となる可能性を検証する。

Outline of Final Research Achievements

Parkinson's disease has been suggested to be a type of "prion disease" in which α-Synuclein aggregates propagate and spread through neural circuits. Pathological analysis indicates that the gastrointestinal plexus is one of the most possible candidates for the starting point of α-Synuclein aggregation. In this project, we analyzed the possibility and conditions for the propagation of diet-derived α-Synuclein aggregates in Drosophila as a model. The results suggest that diet-derived α-Synuclein aggregates reach neuronal terminals and that inflammation of the gastrointestinal tract enhances the risk of PD.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病はα-Synucleinの凝集が数十年にわたり神経回路を伝播し広がっていく全身性の神経変性疾患であると考えられている。本研究で消化管炎症がα-Synuclein凝集の末梢神経終末への到達リスクになることが示唆された。α-Synuclein凝集は、モデル動物にて種間を超えて伝播する可能性が示唆されている。更なる研究が必要であるが、食事からのα-Synuclein凝集の感染・消化管炎症をパーキンソン病のリスクとして考慮していく必要性を提起するものである。

Research Products

• [Journal Article] Is Glial Dysfunction the Key Pathogenesis of LRRK2-Linked Parkinson’s Disease? (2023)
  • Author(s): Iseki Tatou、Imai Yuzuru、Hattori Nobutaka
  • Journal Title: Biomolecules Volume: 13 Issue: 1 Pages: 178-178
  • DOI: 10.3390/biom13010178
  • Peer Reviewed / Open Access
• [Journal Article] Parkinson disease-associated Leucine-rich repeat kinase regulates UNC-104-dependent axonal transport of Arl8-positive vesicles in Drosophila. (2022)
  • Author(s): Inoshita T, Liu J-Y, Taniguchi D, Ishii R, Shiba-Fukushima K, Hattori N, Imai Y.
  • Journal Title: iScience Volume: 25 Issue: 12 Pages: 105476-105476
  • DOI: 10.1016/j.isci.2022.105476
  • Peer Reviewed / Open Access
• [Journal Article] Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson’s disease. (2022)
  • Author(s): Tezuka T, Taniguchi D, Sano M, Shimada T, Oji Y, Tsunemi T, Ikeda A, Li Y, Yoshino H, Ogata J, Shiba-Fukushima K, Funayama M, Nishioka K, Imai Y, Hattori N.
  • Journal Title: NPJ Parkinsons Dis. Volume: 8 Issue: 1 Pages: 97-97
  • DOI: 10.1038/s41531-022-00367-y
  • Peer Reviewed / Open Access
• [Journal Article] α-Synuclein V15A variant in familial Parkinson's disease exhibits a weaker lipid-binding property. (2022)
  • Author(s): Daida K, Shimonaka S, Shiba-Fukushima K, Ogata J, Yoshino H, Okuzumi A, Hatano T, Motoi Y, Hirunagi T, Katsuno M, Shindou H, Funayama M, Nishioka K, Hattori N, Imai Y.
  • Journal Title: Mov Disord. Volume: 37 Issue: 10 Pages: 2075-2085
  • DOI: 10.1002/mds.29162
  • Peer Reviewed / Open Access
• [Journal Article] Ubiquitination at the lysine 27 residue of the Parkin ubiquitin-like domain is suggestive of a new mechanism of Parkin activation. (2022)
  • Author(s): Liu J-Y, Inoshita T, Shiba-Fukushima K, Yoshida K, Ishihama Y, Imai Y, Hattori N.
  • Journal Title: Hum Mol Genet. Volume: 31 Issue: 15 Pages: 2623-2638
  • DOI: 10.1093/hmg/ddac064
  • Peer Reviewed / Open Access
• [Journal Article] Neurodegeneration-associated mitochondrial proteins, CHCHD2 and CHCHD10-what distinguishes the two? (2022)
  • Author(s): Aya Ikeda
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 10 Pages: 1-12
  • DOI: 10.3389/fcell.2022.996061
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Manifestations and Molecular Backgrounds of Parkinson's Disease Regarding Genes Identified From Familial and Population Studies (2022)
  • Author(s): Nishioka Kenya、Imai Yuzuru、Yoshino Hiroyo、Li Yuanzhe、Funayama Manabu、Hattori Nobutaka
  • Journal Title: Frontiers in Neurology Volume: 13 Pages: 764917-764917
  • DOI: 10.3389/fneur.2022.764917
  • Peer Reviewed / Open Access
• [Journal Article] A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels (2021)
  • Author(s): Ogata Jun、Hirao Kentaro、Nishioka Kenya、Hayashida Arisa、Li Yuanzhe、Yoshino Hiroyo、Shimizu Soichiro、Hattori Nobutaka、Imai Yuzuru
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 7 Pages: 3708-3708
  • DOI: 10.3390/ijms22073708
  • Peer Reviewed / Open Access
• [Journal Article] Editorial: Molecular Links Between Mitochondrial Damage and Parkinson's Disease and Related Disorders (2021)
  • Author(s): Imai Yuzuru、Kim Kiyoung、Wu Zhihao、Sato Shigeto
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 9
  • DOI: 10.3389/fcell.2021.734475
  • Open Access / Int'l Joint Research
• [Journal Article] Syntaxin 17, an ancient SNARE paralog, plays different and conserved roles in different organisms (2021)
  • Author(s): Kato Shun、Arasaki Kohei、Tokutomi Natsuki、Imai Yuzuru、Inoshita Tsuyoshi、Hattori Nobutaka、Sasaki Taeko、Sato Miyuki、Wakana Yuichi、Inoue Hiroki、Tagaya Mitsuo
  • Journal Title: Journal of Cell Science Volume: 134 Issue: 22
  • DOI: 10.1242/jcs.258699
  • Peer Reviewed
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1 (2021)
  • Author(s): Daniel J Klionsky、Shu Aizawa、Amal Kamal Abdel-Aziz、Sara Abdelfatah、Mahmoud Abdellatif、Asghar Abdoli、Steffen Abel、Hagai Abeliovich、Marie H Abildgaard、Yakubu Princely Abudu、Abraham Acevedo-Arozena、Iannis E Adamopoulos、Khosrow Adeli、Timon E Adolph、Annagrazia Adornetto、Elma Aflaki、Galila Agam et al.
  • Journal Title: Autophagy Volume: 17 Issue: 1 Pages: 1-382
  • DOI: 10.1080/15548627.2020.1797280
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] UQCRC1 engages cytochrome c for neuronal apoptotic cell death (2021)
  • Author(s): Hung Yu-Chien、Huang Kuan-Lin、Chen Po-Lin、Li Jeng-Lin、Lu Serena Huei-An、Chang Jui-Chih、Lin Han-Yi、Lo Wen-Chun、Huang Shu-Yi、Lee Tai-Ting、Lin Tai-Yi、Imai Yuzuru、Hattori Nobutaka、Liu Chin-San、Tsai Su-Yi、Chen Chun-Hong、Lin Chin-Hsien、Chan Chih-Chiang
  • Journal Title: Cell Reports Volume: 36 Issue: 12 Pages: 109729-109729
  • DOI: 10.1016/j.celrep.2021.109729
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-fat diet-induced activation of SGK1 promotes Alzheimer’s disease-associated tau pathology (2021)
  • Author(s): Elahi Montasir、Motoi Yumiko、Shimonaka Shotaro、Ishida Yoko、Hioki Hiroyuki、Takanashi Masashi、Ishiguro Koichi、Imai Yuzuru、Hattori Nobutaka
  • Journal Title: Human Molecular Genetics Volume: 30 Issue: 18 Pages: 1693-1710
  • DOI: 10.1093/hmg/ddab115
  • Peer Reviewed / Open Access
• [Journal Article] Editorial for the Special Issue “Animal Models of Parkinson’s Disease and Related Disorders” (2020)
  • Author(s): Imai Y
  • Journal Title: Int. J. Mol. Sci. Volume: 21 Issue: 12 Pages: 4250-4250
  • DOI: 10.3390/ijms21124250
  • Open Access
• [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
• [Presentation] 若年性パーキンソン病原因遺伝子産物Parkinの活性化メカニズムの新規知見 (2022)
  • Author(s): 今居 譲
  • Organizer: 第95回日本生化学会大会
  • Invited
• [Presentation] Loss of MPAN-associated C19orf12 causes alteration of lipid metabolism and autophagosome-lysosome trafficking in Drosophila. (2022)
  • Author(s): Shiina K, Mori A, Miki Y, Murakami M, Ueno N, Miura Y, Hatano T, Imai Y, Hattori N
  • Organizer: 8th International symposium on NBIA
  • Int'l Joint Research
• [Presentation] Two novel variants in CHCHD2 associate with TDP-43 pathology among amyotrophic lateral sclerosis. (2022)
  • Author(s): Ikeda A, Funayama M, Yoshida M, Li Y, Inoshita T, Shiba-Fukushima K, Meng H, Amo T, Aiba I, Saito Y, Atsuta N, Nakamura R, Tohnai G, Sone J, Izumi Y, Kaji R, Morita M, Taniguchi A, Nishioka K, Imai Y, Sobue G, Hattori N, JaCALS
  • Organizer: 第63回日本神経学会学術大会
• [Presentation] Loss of MPAN-associated C19orf12 causes alteration of lipid metabolism in Drosophila. (2022)
  • Author(s): Shiina K, Mori A, Miki Y, Murakami M, Ueno N, Miura Y, Hatano T, Imai Y, Hattori N
  • Organizer: 第63回日本神経学会学術大会
• [Presentation] Ubiquitination at the lysine 27 residue of the Parkin ubiquitin-like domain is suggestive of a new mechanism of Parkin activation. (2022)
  • Author(s): Liu J-Y, Inoshita T, Shiba-Fukushima K, Hattori N, Imai Y
  • Organizer: Neuro2022
• [Presentation] Drosophila VPS13 regulates neuronal synaptic activity and mitochondrial homeostasis. (2022)
  • Author(s): Shiba-Fukushima K, Inoshita T, Imai Y, Hattori N
  • Organizer: Neuro2022
• [Presentation] Screening of lipid species and associated enzymes that participate in α-synuclein aggregation. (2022)
  • Author(s): Kasahara R, Ogata J, Shiina K, Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y
  • Organizer: MBSJ2022
• [Presentation] ミトコンドリア変性とパーキンソン病 (2021)
  • Author(s): 今居 譲
  • Organizer: 第20回日本ミトコンドリア学会年会
  • Invited
• [Presentation] αシヌクレインの凝集要因、生体膜脂質とミトコンドリア (2021)
  • Author(s): 今居 譲
  • Organizer: 第35回日本大脳基底核研究会
  • Invited
• [Presentation] Mechanism of α-Synuclein aggregation by the disturbance of biomembrane remodelling. (2020)
  • Author(s): Yuzuru Imai
  • Organizer: LIFS Seminar Series”, at Devision of Life Science, Hong Kong University of Science and Technology
  • Int'l Joint Research / Invited
• [Presentation] パーキンソン病病態に関与するリン脂質変化 (2020)
  • Author(s): 今居 譲
  • Organizer: 第 63 回日本神経化学会大会 公募シンポジウム７「脂質が制御する神経機能」
  • Invited
• [Book] Experimental Models of Parkinson’s Disease. (2021)
  • Author(s): Imai Y
  • Total Pages: 228
  • Publisher: Humana Press
• [Remarks] パーキンソン病病態解明研究講座 研究
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/parkinsons_disease/k4.html
• [Remarks] 順天堂大学大学院 医学研究科 パーキンソン病病態解明研究講座
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/parkinsons_disease/
• [Remarks] 順天堂大学 パーキンソン病病態解明研究講座
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/parkinsons_disease/
• [Remarks] 順天堂大学 パーキンソン病病態解明研究講座 研究紹介動画
  • URL: https://www.juntendo.ac.jp/news/20200325-02.html