Investigating the pathogenesis and development of therapeutics of alpha-synucleinopathy

• Project/Area Number: 18H04041
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Kyoto University
• Principal Investigator: Takahashi Ryosuke 京都大学, 医学研究科, 教授 (90216771)
• Co-Investigator(Kenkyū-buntansha): 秋山 央子 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (80623462)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥31,850,000 (Direct Cost: ¥24,500,000、Indirect Cost: ¥7,350,000); Fiscal Year 2020: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000); Fiscal Year 2019: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2018: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
• Keywords: パーキンソン病 / 多系統萎縮症 / αシヌクレイン / glucocerebrosidase

Outline of Final Research Achievements

Analysis of the two mice model for idiopathic Parkinson’s disease (PD), a-syn BAC Tg/GBA1 heterozygous KO mice and A53T mutant a-syn BAC Tg mice, revealed the region-specific increase in the amount of various kind of glycolipids, and cellular experiment suggested the conformational change of a-syn by altered lipid metabolism. To investigate the role of GBA2 gene as a modifier of GBA1 gene, we generated GBA2-/- (KO) medaka fish and GBA1/GBA2 double knockout medaka fish, and found that GBA2 deletion further increased the amount of specific glycolipids. Moreover, GBA1 was found to function as β-galactosidase, a GalCer degrading enzyme.

Academic Significance and Societal Importance of the Research Achievements

モデル動物を使用した実験からパーキンソン病において脂質代謝異常がαシヌクレインの修飾を介して病態に関与しうること、孤発性パーキンソン病の最大の遺伝的リスク因子であるGBA１の修飾因子としてGBA2が存在することなどが判明し、治療のターゲット分子となりうることを示した。

Research Products

• [Journal Article] Synaptic Vesicle Protein 2B Negatively Regulates the Amyloidogenic Processing of AβPP as a Novel Interaction Partner of BACE1 (2020)
  • Author(s): Miyamoto Masakazu、Kuzuya Akira、Noda Yasuha、Ueda Sakiho、Asada-Utsugi Megumi、Ito Shinji、Fukusumi Yoshiyasu、Kawachi Hiroshi、Takahashi Ryosuke、Kinoshita Ayae
  • Journal Title: Journal of Alzheimer's Disease Volume: Apr 6 Issue: 1 Pages: 1-13
  • DOI: 10.3233/jad-200071
  • Peer Reviewed
• [Journal Article] Animal Model for Prodromal Parkinson’s Disease (2020)
  • Author(s): Taguchi Tomoyuki、Ikuno Masashi、Yamakado Hodaka、Takahashi Ryosuke
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 6 Pages: 1961-1961
  • DOI: 10.3390/ijms21061961
  • NAID: 120006844881
  • Peer Reviewed / Open Access
• [Journal Article] Glucocerebrosidases catalyze a transgalactosylation reaction that yields a newly-identified brain sterol metabolite, galactosylated cholesterol (2020)
  • Author(s): Akiyama, H., Ide, M., Nagatsuka, Y., Sayano, T., Nakanishi, E., Uemura, N., Yuyama, K., Yamaguchi, Y., Kamiguchi, H., Takahashi, R., Aerts, J. M. F. G., Greimel, P. and Hirabayashi, Y
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 16 Pages: 5257-5277
  • DOI: 10.1074/jbc.ra119.012502
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions (2020)
  • Author(s): Kaji Seiji、Maki Takakuni、Ishimoto Tomoyuki、Yamakado Hodaka、Takahashi Ryosuke
  • Journal Title: Translational Neurodegeneration Volume: 9 Issue: 1 Pages: 1-2
  • DOI: 10.1186/s40035-020-0185-5
  • Peer Reviewed / Open Access
• [Journal Article] Reduced Enhancement of Memory for Faces Encoded by Semantic and Socioemotional Processes in Patients with Parkinson's Disease (2020)
  • Author(s): Park P., Yamakado H., Takahashi R., Dote S., Ubukata S., Murai T., Tsukiura T.
  • Journal Title: Journal of the International Neuropsychological Society (JINS) Volume: 26 Issue: 4 Pages: 418-429
  • DOI: 10.1017/s1355617719001280
  • 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] Limited spread of pathology within the brainstem of α-synuclein BAC transgenic mice inoculated with preformed fibrils into the gastrointestinal tract. (2020)
  • Author(s): Uemura N, Yagi H, Uemura MT, Yamakado H, Takahashi R.
  • Journal Title: Neurosci Lett. Volume: 716 Pages: 134651-134651
  • DOI: 10.1016/j.neulet.2019.134651
  • Peer Reviewed
• [Journal Article] 6-Deoxyjacareubin, a natural compound preventing hypoxia-induced cell death, ameliorates neurodegeneration in a mouse model of familial amyotrophic lateral sclerosis (2020)
  • Author(s): Hoshino Tomonori、Matsuzawa Shu-ichi、Takahashi Ryosuke
  • Journal Title: Neuroscience Research Volume: 1 Pages: 1-2
  • DOI: 10.1016/j.neures.2020.02.011
  • Peer Reviewed
• [Journal Article] Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (α-Syn) Pathology in Synthetic α-Syn Fibril-Induced Mouse Models of Synucleinopathy (2019)
  • Author(s): Uemura Norihito、Uemura Maiko T、Lo Angela、Bassil Fares、Zhang Bin、Luk Kelvin C、Lee Virginia M -Y、Takahashi Ryosuke、Trojanowski John Q
  • Journal Title: Journal of Neuropathology & Experimental Neurology Volume: 78 Issue: 10 Pages: 877-890
  • DOI: 10.1093/jnen/nlz070
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] KUS121, a valosin-containing protein modulator, attenuates ischemic stroke via preventing ATP depletion. (2019)
  • Author(s): Kinoshita H, Maki T, Yasuda K, Kishida N, Sasaoka N, Takagi Y, Kakizuka A, Takahashi R.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 11519-11519
  • DOI: 10.1038/s41598-019-47993-w
  • NAID: 120006786947
  • Peer Reviewed / Open Access
• [Journal Article] Value of in vivo α‐synuclein deposits in Parkinson's disease: A systematic review and meta‐analysis (2019)
  • Author(s): Tsukita Kazuto、Sakamaki‐Tsukita Haruhi、Tanaka Kanta、Suenaga Toshihiko、Takahashi Ryosuke
  • Journal Title: Movement Disorders Volume: 34 Issue: 10 Pages: 1452-1463
  • DOI: 10.1002/mds.27794
  • Peer Reviewed
• [Journal Article] Real-world pharmacological treatment patterns of patients with young-onset Parkinson’s disease in Japan: a medical claims database analysis (2019)
  • Author(s): Kasamo Sachiko、Takeuchi Masato、Ikuno Masashi、Kawasaki Yohei、Tanaka Shiro、Takahashi Ryosuke、Kawakami Koji
  • Journal Title: Journal of Neurology Volume: 266 Issue: 8 Pages: 1944-1952
  • DOI: 10.1007/s00415-019-09360-7
  • Peer Reviewed
• [Journal Article] GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson’s disease (2019)
  • Author(s): Ikuno Masashi、Yamakado Hodaka、Akiyama Hisako、Parajuli Laxmi Kumar、Taguchi Katsutoshi、Hara Junko、Uemura Norihito、Hatanaka Yusuke、Higaki Katsumi、Ohno Kousaku、Tanaka Masaki、Koike Masato、Hirabayashi Yoshio、Takahashi Ryosuke
  • Journal Title: Human Molecular Genetics Volume: 印刷中 Issue: 11 Pages: 1894-1904
  • DOI: 10.1093/hmg/ddz030
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Newly identified brain sterol metabolite glycosylated sterols are metabolized by α-glucocerebrosidase 1 and 2 in vivo (2019)
  • Author(s): Hisako Akiyama, Mitsuko Ide, Etsuro Nakanishi, Norihito Uemura, Yoshiki Yamaguchi, Hiroyuki Kamiguchi, Ryosuke Takahashi, Peter Greimel and Yoshio Hirabayashi
  • Organizer: 25th International Symposium on Glycoconjugates, Milan, Italy,
  • Int'l Joint Research
• [Presentation] Glucocerebrosidase mediates a crosstalk between glycosphingolipid and sterol (2019)
  • Author(s): Hisako Akiyama
  • Organizer: 1st Japan-Europe Workshop on Glycosphingolipids and Membrane Homeostasis, Strasbourg, France
  • Int'l Joint Research
• [Presentation] グルコシルセラミド分解酵素による新規脳内ステロール代謝物・ステロール配糖体の代謝制御 (2019)
  • Author(s): 秋山央子、井手三津子、中西悦郎、上村紀仁、山口芳樹、Peter Greimel、上口裕之、高橋良輔、平林義雄
  • Organizer: 第92回 日本生化学会大会、横浜市、神奈川県
• [Remarks] 京都大学医学部附属病院・脳神経内科
  • URL: http://neurology.kuhp.kyoto-u.ac.jp/index.html
• [Remarks] 京都大学大学院医学研究科・臨床神経学
  • URL: http://www.med.kyoto-u.ac.jp/organization-staff/research/doctoral_course/r-059/