Elucidation of the mechanisms of the Parkinson's disease genes and Lewy Body formation and alpha-synuclein propagation mechanisms
Project/Area Number |
18H04043
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Medium-sized Section 52:General internal medicine and related fields
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Research Institution | Juntendo University |
Principal Investigator |
Hattori Nobutaka 順天堂大学, 医学(系)研究科(研究院), 教授 (80218510)
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥44,720,000 (Direct Cost: ¥34,400,000、Indirect Cost: ¥10,320,000)
Fiscal Year 2020: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
Fiscal Year 2019: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
Fiscal Year 2018: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000)
|
Keywords | パーキンソン病 / α-シヌクレイン / SNCA / Lewy小体 / ミトコンドリア / オートファジー / CHCHD2 / PLA2G6 / レヴィ小体 / SNCA / 遺伝性パーキンソン病 / α-synuclein / 脂質組成 / 遺伝子解析 / 神経細胞死 / 伝播形式 |
Outline of Final Research Achievements |
In models of CHCHD2 knockout flies, knockout mice, and patient-derived iPS cells, mitochondrial function declines in an age-dependent manner, forming SNCA-positive Lewy body-like inclusion bodies. Furthermore, analysis of PLA2G6 knockout flies showed shortening of the acyl group of brain phospholipids. It was clarified that the homeostasis of mitochondrial protein and phospholipid composition is the primary cause of the mechanism of aggregate formation in Parkinson's disease.
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Academic Significance and Societal Importance of the Research Achievements |
封入体を形成する遺伝性パーキンソン病に着目し、モデル動物の解析により封入体形成のメカニズム解明に迫ることができた。本研究の成果は多くを占める孤発性パーキンソン病の病態解明につながるものであり、今後の疾患予防や治療法開発に向けて基礎的な知見となる。
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Report
(4 results)
Research Products
(61 results)
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[Journal Article] The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.2021
Author(s)
Hayashida A, Li Y, Yoshino H, Daida K, Ikeda A, Ogaki K, Fuse A, Mori A, Takanashi M, Nakahara T, Hattori Y, Hattori T, Ichinose Y, Takiyama Y, Saito T, Kimura T, Aizawa H, Shoji H, Mizuno Y, Matsushita T, Sato M, Sekijima Y, Morita M, Iwasaki A, Kusaka H, Tada M, Funayama M, Nishioka K, Hattori N, et al.
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Journal Title
Neurobiol Aging.
Volume: 97
Pages: 146.e1-146.e13
DOI
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Peer Reviewed
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[Journal Article] Reduced astrocytic reactivity in human brains and midbrain organoids with PRKN mutations.2020
Author(s)
Kano M, Takanashi M, Oyama G, Yoritaka A, Hatano T, Shiba-Fukushima K, Nagai M, Nishiyama K, Hasegawa K, Inoshita T, Ishikawa KI, Akamatsu W, Imai Y, Bolognin S, Schwamborn JC, Hattori N.
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Journal Title
NPJ Parkinsons Dis.
Volume: 13
Pages: 33
DOI
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Peer Reviewed
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[Journal Article] Identifying Therapeutic Agents for Amelioration of Mitochondrial Clearance Disorder in Neurons of Familial Parkinson Disease.2020
Author(s)
Yamaguchi A, Ishikawa KI, Inoshita T, Shiba-Fukushima K, Saiki S, Hatano T, Mori A, Oji Y, Okuzumi A, Li Y, Funayama M, Imai Y, Hattori N, Akamatsu W.
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Journal Title
Stem Cell Reports.
Volume: 14
Pages: 1060-1075
DOI
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Peer Reviewed
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[Journal Article] Variants in saposin D domain of prosaposin gene linked to Parkinson's disease. Brain.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, Ichinose Y, Koh K, Shindo K, Takiyama Y, Hamaguchi T, Farrer MJ, Uchiyama Y, Wu YR, Hattori N, et al.
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Journal Title
Brain
Volume: 143
Pages: 1190-1205
DOI
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Peer Reviewed / Int'l Joint Research
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[Journal Article] Neuromelanin or DaT-SPECT: which is the better marker for discriminating advanced Parkinson's disease?2020
Author(s)
Okuzumi A, Hatano T, Kamagata K, Hori M, Mori A, Oji Y, Taniguchi D, Daida K, Shimo Y, Yanagisawa N, Nojiri S, Aoki S, Hattori N.
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Journal Title
Eur J Neurol.
Volume: 26
Pages: 1408-1416
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Peer Reviewed
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[Journal Article] Pathological findings in a patient with alpha-synuclein p.A53T and familial Parkinson's disease.2020
Author(s)
Nishioka K, Hashizume Y, Takanashi M, Daida K, Li Y, Yoshino H, Tambasco N, Prontera P, Hattori Y, Ueda A, Watanabe H, Hattori N.
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Journal Title
Parkinsonism Relat Disord.
Volume: 81
Pages: 183-187
DOI
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Peer Reviewed
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[Journal Article] Nonmercaptalbumin as an oxidative stress marker in Parkinson's and PARK2 disease.2020
Author(s)
Ueno SI, Hatano T, Okuzumi A, Saiki S, Oji Y, Mori A, Koinuma T, Fujimaki M, Takeshige-Amano H, Kondo A, Yoshikawa N, Nojiri T, Kurano M, Yasukawa K, Yatomi Y, Ikeda H, Hattori N.
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Journal Title
Ann Clin Transl Neurol.
Volume: 7
Pages: 307-317
DOI
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Peer Reviewed
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[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, Ichinose Y, Koh K, Shindo K, Takiyama Y, Hamaguchi T, Yamada M, Farrer MJ, Uchiyama Y, , Wu YR, Hattori N、et al.
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Journal Title
Brain.
Volume: 2020 Mar 23
Pages: awaa064
DOI
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Peer Reviewed / Int'l Joint Research
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[Journal Article] Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features.2019
Author(s)
Ikeda A, Shimada H, Nishioka K, Takanashi M, Hayashida A, Li Y, Yoshino H, Funayama M, Ueno Y, Hatano T, Sahara N, Suhara T, Higuchi M, Hattori N.
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Journal Title
Mov Disord.
Volume: 34
Pages: 568-574
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Peer Reviewed
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[Journal Article] A metabolic profile of polyamines in parkinson disease: A promising biomarker.2019
Author(s)
Saiki S, Sasazawa Y, Fujimaki M, Kamagata K, Kaga N, Taka H, Li Y, Souma S, Hatano T, Imamichi Y, Furuya N, Mori A, Oji Y, Ueno SI, Nojiri S, Miura Y, Ueno T, Funayama M, Aoki S, Hattori N.
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Journal Title
Ann Neurol.
Volume: 86
Pages: 251-263
DOI
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Peer Reviewed
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[Journal Article] Plasma metabolite biomarkers for multiple system atrophy and progressive supranuclear palsy.2019
Author(s)
Mori A, Ishikawa KI, Saiki S, Hatano T, Oji Y, Okuzumi A, Fujimaki M, Koinuma T, Ueno SI, Imamichi Y, Hattori N.
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Journal Title
PLoS One.
Volume: 14
Pages: e0223113.
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Peer Reviewed
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[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.
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Journal Title
Proc Natl Acad Sci U S A.
Volume: 116
Pages: 20689-20699
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Peer Reviewed
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[Journal Article] Mutations in CHCHD2 cause α-synuclein aggregation.2019
Author(s)
Ikeda A, Nishioka K, Meng H, Takanashi M, Hasegawa I, Inoshita T, Shiba-Fukushima K, Li Y, Yoshino H, Mori A, Okuzumi A, Yamaguchi A, Nonaka R, Izawa N, Ishikawa KI, Saiki H, Morita M, Hasegawa M, Hasegawa K, Elahi M, Funayama M, Okano H, Akamatsu W, Imai Y, Hattori N.
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Journal Title
Hum Mol Genet.
Volume: 28
Pages: 3895-3911
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Peer Reviewed
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[Journal Article] Metabolomics-based identification of metabolic alterations in PARK2.2019
Author(s)
Okuzumi A, Hatano T, Ueno SI, Ogawa T, Saiki S, Mori A, Koinuma T, Oji Y, Ishikawa KI, Fujimaki M, Sato S, Ramamoorthy S, Mo hney RP, Hattori N.
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Journal Title
Ann Clin Transl Neurol.
Volume: 6
Pages: 525-536.
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[Journal Article] Zonisamide Administration Improves Fatty Acid β-Oxidation in Parkinson’s Disease2018
Author(s)
Ueno SI, Saiki S, Fujimaki M, Takeshige-Amano H, Hatano T, Oyama G, Ishikawa KI, Yamaguchi A, Nojiri S, Akamatsu W, Hattori N.
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Journal Title
Cells
Volume: 8
Pages: 14-14
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Peer Reviewed
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[Journal Article] Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy2018
Author(s)
Sugo M, Kimura H, Arasaki K, Amemiya T, Hirota N, Dohmae N, Imai Y, Inoshita T, Shiba-Fukushima K, Hattori N, Cheng J, Fujimoto T, Wakana Y, Inoue H, Tagaya M.
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Journal Title
The EMBO Journal
Volume: 37
Pages: e98899-e98899
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Peer Reviewed
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[Journal Article] Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment2018
Author(s)
Okuzumi A, Kurosawa M, Hatano T, Takanashi M, Nojiri S, Fukuhara T, Yamanaka T, Miyazaki H, Yoshinaga S, Furukawa Y, Shimogori T, Hattori N, Nukina N.
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Journal Title
Acta Neuropathologica Communications
Volume: 6
Pages: 96-96
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Peer Reviewed
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[Journal Article] Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease.2018
Author(s)
Fujimaki M, Saiki S, Li Y, Kaga N, Taka H, Hatano T, Ishikawa KI, Oji Y, Mori A, Okuzumi A, Koinuma T, Ueno SI, Imamichi Y, Ueno T, Miura Y, Funayama M, Hattori N.
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Journal Title
Neurology
Volume: 90
Pages: 404-411
DOI
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Peer Reviewed
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