Aim to identify a novel gene related to familial Parkinson's disease

• Project/Area Number: 20K07893
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Juntendo University
• Principal Investigator: Nishioka Kenya 順天堂大学, 医学部, 先任准教授 (40348933)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Parkinson's disease / Whole genome sequencing / Long read sequencing / Whole exome sequencing / 家族性パーキンソン病 / 臨床遺伝学 / 遺伝子 / 全ゲノムシーケンス / 全エクソームシーケンス / パーキンソン病 / 遺伝子変異 / 次世代シーケンサー

Outline of Research at the Start

パーキンソン病（PD）は、神経変性疾患では、アルツハイマー病に次いで多い。これまでに遺伝性PDの研究から同定された遺伝子群は、Genome-wide association studyを用いた大規模メタ解析にて、孤発型PDにも強く関連することが証明されている。今回代表者は常染色体優性遺伝形式をとり、既知の遺伝子変異を持たないPD の一家系に注目し、全ゲノムシーケンスを施行し、１つの病的候補遺伝子Xまで絞り込めている。今後はその遺伝子の機能解析に移行し、その遺伝子が真に病的なものかどうかの立証作業を進める。最終目標は、新規病的遺伝子の単離を目指し、その分子病態の全貌を解明する。

Outline of Final Research Achievements

We performed the DNA analyses for a familial Parkinson's disease (PD) with autosomal dominant inheritance, along with targeted sequencing, whole genome sequencing and whole exome sequencing. We identified six candidate genes (FSD1，CDRT15L2，AP2A2, TALDO1, SLC22A3, FBLN2), however our additional analyses did not prove the pathogenicity among them. Next, we aim to analyze structural variants using long read sequencing, collaborating with Yokohama city university.

Academic Significance and Societal Importance of the Research Achievements

三世代に渡り同一家系内に濃厚な発症者をもつ一家系に焦点を絞り，解析を行った。Whole genome sequencingとwhole exome sequencingを用いて候補領域を同定し，また候補となった遺伝子には，DNA bankからのサンプルとtargeted resequencingを施行したが，病的遺伝子の同定には至らなかった。点変異では説明の付かない変異の可能性を考え，次に構造多型に注目し，現在PacBio社のSequel IIシークエンサーを利用したLong Read Sequencingを行っている。新たなパーキンソン病の原因遺伝子の同定に向けて解析を行っている。

Research Products

• [Journal Article] Analysis of LIN28A variants in patients with Parkinson’s disease (2023)
  • Author(s): Peng Hao、Li Yuanzhe、Yoshino Hiroyo、Shimizu Mai、Nishioka Kenya、Funayama Manabu、Hattori Nobutaka
  • Journal Title: Journal of Human Genetics Volume: 68 Issue: 5 Pages: 329-331
  • DOI: 10.1038/s10038-022-01109-x
  • Peer Reviewed
• [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] 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] Genotype-phenotype correlation of Parkinson's disease with PRKN variants (2022)
  • Author(s): Yoshino Hiroyo、Li Yuanzhe、Nishioka Kenya、Daida Kensuke、Hayashida Arisa、Ishiguro Yuta、Yamada Daisuke、Izawa Nana、Nishi Katsunori、Nishikawa Noriko、Oyama Genko、Hatano Taku、Nakamura Shinichiro、Yoritaka Asako、Motoi Yumiko、Funayama Manabu、Hattori Nobutaka
  • Journal Title: Neurobiology of Aging Volume: 114 Pages: 117-128
  • DOI: 10.1016/j.neurobiolaging.2021.12.014
  • Peer Reviewed
• [Journal Article] Generation of three hiPSC clones from a Parkinson's disease patient with a heterozygous variant of VPS35 p.D620N (2022)
  • Author(s): Kei-Ichi Ishikawa, Mayu Ishiguro, Yuanzhe Li , Kenya Nishioka, Nobutaka Hattori, Wado Akamatsu
  • Journal Title: Stem Cell Research Volume: 60 Pages: 102739-102739
  • DOI: 10.1016/j.scr.2022.102739
  • Peer Reviewed / Open Access
• [Journal Article] A complex form of hereditary spastic paraplegia harboring a novel variant, p.W1515*, in the SPG11 gene (2022)
  • Author(s): Daida Kensuke、Nishioka Yosuke、Li Yuanzhe、Yoshino Hiroyo、Funayama Manabu、Hattori Nobutaka、Nishioka Kenya
  • Journal Title: eNeurologicalSci Volume: 26 Pages: 100391-100391
  • DOI: 10.1016/j.ensci.2021.100391
  • Peer Reviewed / Open Access
• [Journal Article] Genetic analysis of ATP10B for Parkinson's disease in Japan (2021)
  • Author(s): Ishiguro Mayu、Yoshino Hiroyo、Li Yuanzhe、Ikeda Aya、Funayama Manabu、Nishioka Kenya、Hattori Nobutaka
  • Journal Title: Parkinsonism and Related Disorders Volume: 88 Pages: 10-12
  • DOI: 10.1016/j.parkreldis.2021.05.020
  • Peer Reviewed
• [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] Clinical manifestations of Parkinson's disease harboring VPS35 retromer complex component p.D620N with long-term follow-up (2021)
  • Author(s): Ishiguro Mayu、Li Yuanzhe、Yoshino Hiroyo、Daida Kensuke、Ishiguro Yuta、Oyama Genko、Saiki Shinji、Funayama Manabu、Hattori Nobutaka、Nishioka Kenya
  • Journal Title: Parkinsonism & Related Disorders Volume: 84 Pages: 139-143
  • DOI: 10.1016/j.parkreldis.2021.02.014
  • Peer Reviewed
• [Journal Article] PLA2G6 variants associated with the number of affected alleles in Parkinson’s disease in Japan (2021)
  • Author(s): Daida Kensuke、Nishioka Kenya、Li Yuanzhe、Yoshino Hiroyo、Shimada Tomoyo、Dougu Nobuhiro、et al.
  • Journal Title: Neurobiology of Aging Volume: 97 Pages: 1-9
  • DOI: 10.1016/j.neurobiolaging.2020.07.004
  • Peer Reviewed
• [Journal Article] The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1 (2021)
  • Author(s): Hayashida Arisa、Li Yuanzhe、Yoshino Hiroyo、Daida Kensuke、Ikeda Aya、et al.
  • Journal Title: Neurobiology of Aging Volume: 97 Pages: 3301-3301
  • DOI: 10.1016/j.neurobiolaging.2020.06.017
  • Peer Reviewed / Open Access
• [Journal Article] Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease (2021)
  • Author(s): Mishima T, Fujioka S, Nishioka K, Li Y, Sato K, Houzen H, Yabe I, Shiomi K, Eriguchi M, Hara H, Hattori N, Tsuboi Y.
  • Journal Title: Parkinsonism and related disorders Volume: In press Pages: 49-53
  • DOI: 10.1016/j.parkreldis.2020.12.017
  • Peer Reviewed
• [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.
  • Journal Title: Parkinsonism and related disorders Volume: In press Pages: 183-187
  • DOI: 10.1016/j.parkreldis.2020.11.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy (2020)
  • Author(s): Lin Chin-Hsien、Tsai Pei-I、Lin Han-Yi、Hattori Nobutaka、Funayama Manabu、Jeon Beomseok、et al.
  • Journal Title: Brain Volume: 143 Issue: 11 Pages: 3352-3373
  • DOI: 10.1093/brain/awaa279
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of Disease-Associated Variants by Targeted Gene Panel Resequencing in Parkinson's Disease (2020)
  • Author(s): Daida Kensuke、Funayama Manabu、Li Yuanzhe、Yoshino Hiroyo、Hayashida Arisa、Ikeda Aya、Ogaki Kotaro、Nishioka Kenya、Hattori Nobutaka
  • Journal Title: Frontiers in Neurology Volume: 11 Pages: 576465-576465
  • DOI: 10.3389/fneur.2020.576465
  • Peer Reviewed / Open Access
• [Journal Article] A novel rare variant of LRRK2 associated with familial Parkinson's disease: p.R1501W (2020)
  • Author(s): Masuzugawa S, Nishioka K, Imai Y, Ogata J, Shojima Y, Li Y, Yoshino H, Hattori N.
  • Journal Title: Parkinsonism and Related Disorders. Volume: 76 Pages: 46-48
  • DOI: 10.1016/j.parkreldis.2020.05.035
  • 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
• [Presentation] SNCA p.V15A a novel pathogenic variant for familial Parkinson’s disease (2022)
  • Author(s): Kensuke Daida, Shotaro Shimonaka, Kahori Shiba-Fukushima, Jun Ogata, Hiroyo Yoshino, Ayami Okuzumi, Taku Hatano, Yumiko Motoi, Manabu Funayama, Tomoki Hirunagi, Kentaro Sahashi, Masao Katsuno, Kenya Nishioka, Yuzuru Imai, Nobutaka Hattori
  • Organizer: 第６３回日本神経学会学術大会
• [Presentation] Two novel variants in CHCHD2 associate with TDP-43 pathology among amyotrophic lateral sclerosis (2022)
  • Author(s): Aya Ikeda, Manabu Funayama, Mari Yoshida, Kenya Nishioka et al.
  • Organizer: 第６３回日本神経学会学術大会
• [Presentation] 白質脳症の画像を呈する患者群へのNOTCH3, HTRA1遺伝子変異の解析 (2022)
  • Author(s): 西岡健弥 李元哲 吉野浩代 服部信孝
  • Organizer: Stroke 2022
• [Presentation] SNCA p.V15A a novel pathogenic variant for familial Parkinson’s disease (2022)
  • Author(s): Kensuke Daida , Shotaro Shimonaka , Kahori Shiba-Fukushima , Jun Ogata , Hiroyo Yoshino , Ayami Okuzumi, Taku Hatano, Yumiko Motoi, Manabu Funayama, Tomoki Hirunagi, Kentaro Sahashi , Masao Katsuno , Kenya Nishioka, Yuzuru Imai, Nobutaka Hattori.
  • Organizer: 第63会日本神経学会学術大会
• [Presentation] Two novel variants in CHCHD2 associate with TDP-43 pathology among amyotrophic lateral sclerosis (2022)
  • Author(s): Aya Ikeda, Manabu Funayama, Mari Yoshida, Kenya Nishioka, et al.
  • Organizer: 第63会日本神経学会学術大会
• [Presentation] Genetic screening by panel sequencing of glucosylceramidase beta variants for Parkinson’s disease (2021)
  • Author(s): Yuanzhe Li, Hiroyo Yoshino, Manabu Funayama, Kenya Nishioka, Nobutaka Hattori
  • Organizer: 第62会日本神経学会学術大会
• [Presentation] Pathological findings in a patient with alpha-synuclein p.A53T and familial Parkinson's disease (2021)
  • Author(s): Kenya Nishioka, Yoshio Hashizume, Masashi Takanashi, et al.
  • Organizer: 第62会日本神経学会学術大会