Detection of genetic modifiers in PRKN

• Project/Area Number: 17K14966
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Juntendo University
• Principal Investigator: Ogaki Kotaro 順天堂大学, 医学部, 准教授 (20459035)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: パーキンソン病 / 遺伝子 / 疾患修飾遺伝子 / parkin / 神経科学 / 次世代シーケンサー / 神経内科

Outline of Final Research Achievements

In this study, we investigated whether disease modifier genes are associated with the onset of PD with heterozygous PRKN mutations. We performed targeted sequencing and sequenced the genes which are previously known as PD genes, functionally associated with PRKN protein, and associated with lysosomal storage disease (total 79 genes). We enrolled 3 groups (total 285 subjects): (i) PD with heterozygous PRKN mutations (n=50), (ii) PD with homozygous mutations whose parents are not PD (n=105), (iii) healthy controls (n=130).The frequency of variant A in Gene X was significantly increased in heterozygous PRKN group compared to Healthy control group. (19% vs 10%, P=0.035, OR 2.02, 95%CI 1.00-4.00). We found a potential genetic modifier of PRKN, Variant A in Gene X as a risk factor. Gene A was previously reported to protect against neuronal death in cellular Parkinson‘s disease models by maintaining levels of PRKN. Further studies are warranted to confirm the genetic modifiers of PRKN.

Academic Significance and Societal Importance of the Research Achievements

当研究室より報告されたparkin遺伝子変異は、若年性PD患者の原因遺伝子としてその頻度は本邦・世界で最多であり、parkin家系において、発症予防法・進行予防法の開発は喫緊の課題である。Gene Aはparkinの発現量を調整することで、PDの細胞モデルで細胞死に対し保護的に働くことが知られている。現在、細胞実験系を用いて gene Xのvariant Aがparkinの発現に与える影響を確認中である。本研究は、parkin 1アレル変異患者の発症予防法・進行予防法開発につながる可能性があり、その社会的意義は大きいと考える。

Research Products

• [Journal Article] Somnolence Preceded the Development of a Subthalamic Lesion in Neuromyelitis Optica Spectrum Disorder (2020)
  • Author(s): Daida Kensuke、Ogaki Kotaro、Hayashida Arisa、Ando Maya、Yokoyama Kazumasa、Noda Kazuyuki、Kanbayashi Takashi、Hattori Nobutaka、Okuma Yasuyuki
  • Journal Title: Internal Medicine Volume: 59 Issue: 4 Pages: 577-579
  • DOI: 10.2169/internalmedicine.2947-19
  • NAID: 130007798428
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-02-15
  • Peer Reviewed / Open Access
• [Journal Article] Neuroimaging evaluation and successful treatment by using directional deep brain stimulation and levodopa in a patient with GNAO1-associated movement disorder: A case report (2020)
  • Author(s): Yamashita Yuri、Ogawa Takashi、Ogaki Kotaro、Kamo Hikaru、Sukigara Tomomi、Kitahara Eriko、Izawa Nana、Iwamuro Hirokazu、Oyama Genko、Kamagata Koji、Hatano Taku、Umemura Atsushi、Kosaki Rika、Kubota Masaya、Shimo Yasushi、Hattori Nobutaka
  • Journal Title: Journal of the Neurological Sciences Volume: 411 Pages: 116710-116710
  • DOI: 10.1016/j.jns.2020.116710
  • Peer Reviewed / Open Access
• [Journal Article] Advanced diffusion magnetic resonance imaging in patients with Alzheimer's and Parkinson's diseases (2020)
  • Author(s): Kamagata Koji、Andica Christina、Hatano Taku、Ogawa Takashi、Takeshige-Amano Haruka、Ogaki Kotaro、Akashi Toshiaki、Hagiwara Akifumi、Fujita Shohei、Aoki Shigeki
  • Journal Title: Neural Regeneration Research Volume: 15 Issue: 9 Pages: 1590-1590
  • DOI: 10.4103/1673-5374.276326
  • Peer Reviewed
• [Journal Article] Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan (2020)
  • Author(s): Li Y、Ikeda A、Yoshino H、Oyama G、Kitani M、Daida K、Hayashida A、Ogaki K、Yoshida K、Kimura T、Nakayama Y、Ito H、Sugeno N、Aoki M、Miyajima H、Kimura K、Ueda N、Watanabe M、Urabe T、Takanashi M、Funayama M、Nishioka K、Hattori N
  • Journal Title: Journal of Human Genetics Volume: ー Issue: 9 Pages: 771-781
  • DOI: 10.1038/s10038-020-0772-4
  • Peer Reviewed
• [Journal Article] Novel GFAP p. Glu206Ala mutation in Alexander disease with decreased dopamine transporter uptake (2020)
  • Author(s): Takashi Ogawa, Kotaro Ogaki, Mayu Ishiguro, Maya And, Tomokatsu Yoshida, Kazuyuki Noda, Nobutaka Hattori, Yasuyuki Okuma.
  • Journal Title: Movement Disorders Clinical Practice Volume: ー
• [Journal Article] Bilateral thigh compartment syndromes from extended sitting with forward bending. (2019)
  • Author(s): Shimada T, Tsunemi T, Hattori A, Nakazato-Taniguchi T, Yasuhara H, Ogaki K, Hattori N
  • Journal Title: J Clin Neurosci Volume: 5868 Pages: 30213-9
  • DOI: 10.1016/j.jocn.2019.03.027
  • Peer Reviewed / Open Access
• [Journal Article] MR biomarkers of degenerative brain disorders derived from diffusion imaging (2019)
  • Author(s): Andica Christina、Kamagata Koji、Hatano Taku、Saito Yuya、Ogaki Kotaro、Hattori Nobutaka、Aoki Shigeki
  • Journal Title: Journal of Magnetic Resonance Imaging Volume: ー Issue: 6 Pages: 1620-1636
  • DOI: 10.1002/jmri.27019
  • Peer Reviewed / Open Access
• [Journal Article] Multiple system atrophy and apolipoprotein E. (2018)
  • Author(s): Ogaki K, Martens YA, Heckman MG, Koga S, Labbe; C, Lorenzo-Betancor O, Wernick AI, Walton RL, Soto AI, Vargas ER, Nielsen HM, Fujioka S, Kanekiyo T, Uitti RJ, van Gerpen JA, Cheshire WP, Wszolek ZK, Low PA, Singer W, Dickson DW, Bu G, Ross OA.
  • Journal Title: Movement Disorder Volume: 33 Issue: 4 Pages: 647-650
  • DOI: 10.1002/mds.27297
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Association study between multiple system atrophy and TREM2 p.R47H. (2018)
  • Author(s): Ogaki K, Heckman MG, Koga S, Martens YA, Labbé C, Lorenzo-Betancor O, Walton RL, Soto AI, Vargas ER, Fujioka S, Uitti RJ, van Gerpen JA, Cheshire WP, Younkin SG, Wszolek ZK, Low PA, Singer W, Bu G, Dickson DW, Ross OA.
  • Journal Title: Neurology Genetics Volume: 4 Issue: 4
  • DOI: 10.1212/nxg.0000000000000257
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Duplication and deletion upstream of LMNB1 in autosomal dominant adult-onset leukodystrophy (2018)
  • Author(s): Mezaki Naomi、Miura Takeshi、Ogaki Kotaro、Eriguchi Makoto、Mizuno Yuri、Komatsu Kenichi、Yamazaki Hiroki、Suetsugi Natsuki、Kawajiri Sumihiro、Yamasaki Ryo、Ishiguro Takanobu、Konno Takuya、Nozaki Hiroaki、Kasuga Kensaku、Okuma Yasuyuki、Kira Jun-Ichi、Hara Hideo、Onodera Osamu、Ikeuchi Takeshi
  • Journal Title: Neurology Genetics Volume: 4 Issue: 6
  • DOI: 10.1212/nxg.0000000000000292
  • Peer Reviewed
• [Journal Article] The PINK1 p.I368N mutation affects protein stability and ubiquitin kinase activity. (2017)
  • Author(s): Ando M, Fiesel FC, Hudec R, Caulfield TR, Ogaki K, Gorka-Skoczylas P, Koziorowski D, Friedman A, Chen L, Dawson VL, Dawson TM, Bu G, Ross OA, Wszolek ZK, Springer W.
  • Journal Title: Mol Neurodegener. Volume: 12 Issue: 1 Pages: 32-32
  • DOI: 10.1186/s13024-017-0174-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reply: Heterozygous PINK1 p.G411S in rapid eye movement sleep behaviour disorder. (2017)
  • Author(s): Puschmann A, Fiesel FC, Caulfield TR, Hudec R, Ando M, Truban D, Hou X, Ogaki K, Heckman MG, James ED, Swanberg M, Jimenez-Ferrer I, Hansson O, Opala G, Siuda J, Boczarska-Jedynak M, Friedman A, Koziorowski D, Aasly JO, Lynch T, Mellick GD, Mohan M, Silburn PA, Sanotsky Y, Vilarino-Guell C, Farrer MJ et al.
  • Journal Title: Brain Volume: in Press Issue: 6 Pages: e33-e33
  • DOI: 10.1093/brain/awx077
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. (2017)
  • Author(s): Puschmann A, Fiesel FC, Caulfield TR, Hudec R, Ando M, Truban D, Hou X, Ogaki K, Heckman MG, James ED, Swanberg M, Jimenez-Ferrer I, Hansson O, Opala G, Siuda J, Boczarska-Jedynak M, Friedman A, Koziorowski D, Aasly JO, Lynch T, Mellick GD, Mohan M, Silburn PA, Sanotsky Y, Vilarino-Guell C, Farrer MJ et al.
  • Journal Title: Brain Volume: 140 Issue: 1 Pages: 98-117
  • DOI: 10.1093/brain/aww261
  • Peer Reviewed / Int'l Joint Research
• [Presentation] プレシジョンメディシスンに遺伝子診断は必要か (2020)
  • Author(s): 大垣光太郎 服部信孝
  • Organizer: 高松国際パーキンソン病シンポジウム 2020
• [Presentation] Genetic analyses of HTRA1 and CTSA in Japanese patients with cerebral small vessel disease (2019)
  • Author(s): Hikaru Kamo, Silvio A. Conedera, Kotaro Ogaki, Kensuke Daida, Yuanzhe Li, Masuo Funabashi, Hiroyo Yoshino, Manabu Funayama, Kenya Nishioka, Nobutaka Hattori
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Detection of genetic modifiers in parkin (2019)
  • Author(s): Kotaro Ogaki, Hirofumi Nakaoka, Kensuke Daida, Arisa Hayashida, Aya Ikeda, Yuanzhe Li, Hiroyo Yoshino, Manabu Funayama, Kenya Nishioka, Ituro Inoue, Nobutaka Hattori
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Genotype-phenotype correlation of LRP10 mutations among familial Parkinson's disease (2019)
  • Author(s): Kensuke Daida, Yuanzhe Li, Manabu Funayama, Kotaro Ogaki, Hiroyo Yoshino, Akio Kikuchi, Fumitaka Hasegawa, Kenya Nishioka, Nobutaka Hattori
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Analysis of intronic region of PRKN in PD with heterozygous PRKN mutation. (2019)
  • Author(s): 大垣光太郎、中岡博史、代田健祐、林田有紗、池田彩、李元哲、吉野浩代、舩山学、西岡健弥、井ノ上 逸朗、服部信孝
  • Organizer: 第13回パーキンソン病・運動障害疾患コングレス
• [Presentation] TREM2 p.R47H may be a risk factor for multiple system atrophy (2018)
  • Author(s): Kotaro Ogaki, Michael G Heckman, Shunsuke Koga, Yuka A. Martens, Catherine Labbe, Oswaldo Lorenzo-Betancor, Ronald L. Walton, Alexandra I. Soto, Emily R. Vargas, Shinsuke Fujioka et al.
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] APOLIPOPROTEIN E: GENETIC ANALYSIS AND FUNCTIONAL STUDY (2018)
  • Author(s): Ogaki K, Martens YA, Heckman MG, Koga S, Labbe C, Lorenzo-Betancor C, Walton RL. , Soto AI, Vargas E, Nielsen HM. , Fujioka S, Kanekiyo T, Uitti RJ, Van Gerpen J, Cheshire WP, Wszolek ZK, Low PA, Singer W, Hattori N, Dickson DW, Bu G, Ross OA
  • Organizer: International Congress of Parkinson's Disease and Movement Disorders 2018
• [Presentation] Detection of genetic modifiers in PRKN (2018)
  • Author(s): Kotaro Ogaki, Hirofumi Nakaoka, Kensuke Daida, Arisa Hayashida, Aya Ikeda, Yuanzhe Li, Hiroyo Yoshino, Manabu Funayama, Kenya Nishioka, Ituro Inoue, Nobutaka Hattori
  • Organizer: The 13th Annual Meeting of Genetic Epidemiology of Parkinson's Disease
• [Presentation] Multiple system atrophy and apolipoprotein E: genetic, pathological and functional analyses (2017)
  • Author(s): Ogaki K, Martens YA, Heckman MG, Koga S, Labbe C, Lorenzo-Betancor C, Walton RL. , Soto AI, Vargas E, Nielsen HM. , Fujioka S, Kanekiyo T, Uitti RJ, Van Gerpen J, Cheshire WP, Wszolek ZK, Low PA, Singer W, Hattori N, Dickson DW, Bu G, Ross OA
  • Organizer: 12th Annual Meeting of Genetic Epidemiology of Parkinson's Disease
  • Int'l Joint Research
• [Presentation] MULTIPLE SYSTEM ATROPHY AND APOLIPOPROTEIN E: GENETIC ANALYSIS AND FUNCTIONAL STUDY (2017)
  • Author(s): Kotaro Ogaki, Yuka A. Martens, Michael G. Heckman, Shunsuke Koga, Shinsuke Fujioka, Takahisa Kanekiyo, Zbigniew K. Wszolek, Wolfgang Singer, Phillip A. Low, Dennis W. Dickson, Nobutaka Hattori, Guojun Bu, Owen A. Ross
  • Organizer: The XXIII World Congress of Neurology
  • Int'l Joint Research
• [Book] 遅発性ジスキネジア［私の治療］ (2020)
  • Author(s): 大垣光太郎, 服部信孝
  • Total Pages: 2
  • Publisher: 日本医事新報社
• [Book] Parkinson病及び関連疾患の治療の進歩 2018. (2019)
  • Author(s): 大垣光太郎 服部信孝
  • Total Pages: 2
  • Publisher: 日本神経治療学会
• [Book] パーキンソン病. 希少疾病ライブラリ (2019)
  • Author(s): 大垣光太郎, 服部信孝
  • Total Pages: 10
  • Publisher: 株式会社ケアネット
• [Book] 新規PD/parkinsonism遺伝子 (劣性および伴性遺伝性など):22q11.2del,SYNJ1,RAB39B,DNAJC6,PODXL,PTRHD1、パーキンソン病(第2版) (2018)
  • Author(s): 大垣光太郎
  • Total Pages: 8
  • Publisher: 日本臨牀社
• [Book] パーキンソン病の遺伝子研究 In: 遺伝子医学MOOK別冊 シリーズ2「最新精神・神経遺伝医学研究と遺伝カウンセリング」 (2017)
  • Author(s): 大垣光太郎、西岡健弥、服部信孝
  • Total Pages: 7
  • Publisher: メディカルドゥ