Elucidation of the pathophysiology related to neuro-glial networks in psychiatric disorders: Toward a pathogenesis-based diagnostic system

• Project/Area Number: 18H04040
• 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: Nagoya University
• Principal Investigator: Ozaki Norio 名古屋大学, 医学系研究科, 教授 (40281480)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥45,370,000 (Direct Cost: ¥34,900,000、Indirect Cost: ¥10,470,000); Fiscal Year 2020: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2018: ¥27,430,000 (Direct Cost: ¥21,100,000、Indirect Cost: ¥6,330,000)
• Keywords: グリア細胞 / 精神障害 / iPS細胞 / モデルマウス / 22q11.2欠失 / ASTN2 / ゲノム / 精神疾患 / オリゴデンドロサイト / 死後脳 / グリア / 統合失調症 / 自閉スペクトラム症 / 双極性障害 / 脳オルガノイド

Outline of Final Research Achievements

In our genomic analysis, we found that rare genomic copy number variations (CNVs) in the glial-related gene ASTN2 are associated with the risk of psychiatric disorders (e.g., bipolar disorder). In gene expression analysis of neurospheres derived from iPS cells with ASTN2 deletion, we also found a marked decrease in expression of the ZNF558, which is suggested to be involved in the pathogenesis of psychiatric disorders. For the 22q11.2 deletion, which is associated with the risk of schizophrenia and glial abnormalities, we revealed a decrease in PERK signaling in midbrain neurons using a mouse model. Furthermore, analysis of brain tissue from schizophrenia patients identified pathological findings suggestive of myelin-oligodendrocyte abnormalities.

Academic Significance and Societal Importance of the Research Achievements

本研究から、グリアに関連する遺伝子が精神障害のリスクに関与することが明らかになった。またモデル生物を用いたゲノム変異の解析から、精神疾患の病態に関与する遺伝子の発現低下や神経発達に必須の細胞内シグナル伝達の低下を明らかにした。統合失調症患者脳組織の解析からもオリゴデンドロサイトと呼ばれるグリア細胞の異常を見出した。以上の知見は、精神障害病態におけるグリア異常の関与を支持するとともに、将来的には、病態に基づいた診断体系の構築や治療法の開発に資することが期待される。

Research Products

• [Journal Article] Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons (2021)
  • Author(s): Arioka Yuko、Shishido Emiko、Kushima Itaru、Suzuki Toshiaki、Saito Ryo、Aiba Atsu、Mori Daisuke、Ozaki Norio
  • Journal Title: EBioMedicine Volume: 63 Pages: 103138-103138
  • DOI: 10.1016/j.ebiom.2020.103138
  • Peer Reviewed / Open Access
• [Journal Article] Structural diverseness of neurons between brain areas and between cases. (2021)
  • Author(s): Mizutani R, Saiga R, Yamamoto Y, Uesugi M, Takeuchi A, Uesugi K, Terada Y, Suzuki Y, De Andrade V, De Carlo F, Takekoshi S, Inomoto C, Nakamura N, Torii Y, Kushima I, Iritani S, Ozaki N, Oshima K, Itokawa M, Arai M.
  • Journal Title: Transl Psychiatry. Volume: 11 Issue: 1 Pages: 49-49
  • DOI: 10.1038/s41398-020-01173-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of a schizophrenia patient with a rare RELN deletion by combining genomic and patient-derived cell analyses (2020)
  • Author(s): Arioka Yuko,Hirata Akihiro,Kushima Itaru,Aleksic Branko,Mori Daisuke,Ozaki Norio
  • Journal Title: Schizophrenia Research Volume: 216 Pages: 511-515
  • DOI: 10.1016/j.schres.2019.10.038
  • Peer Reviewed / Open Access
• [Journal Article] Cell Body Shape and Directional Movement Stability in Human-Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons (2020)
  • Author(s): Arioka Y, Shishido E, Kushima I, Mori D, Ozaki N.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 5820-5820
  • DOI: 10.1038/s41598-020-62598-4
  • Peer Reviewed / Open Access
• [Journal Article] Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia (2020)
  • Author(s): Ishizuka Kanako、Yoshida Tomoyuki、Kawabata Takeshi、Imai Ayako、Mori Hisashi、Kimura Hiroki、Inada Toshiya、Okahisa Yuko、Egawa Jun、Usami Masahide、Kushima Itaru、Morikawa Mako、Okada Takashi、Ikeda Masashi、Branko Aleksic、Mori Daisuke、Someya Toshiyuki、Iwata Nakao、Ozaki Norio
  • Journal Title: Journal of Neurodevelopmental Disorders Volume: 12 Issue: 1 Pages: 25-25
  • DOI: 10.1186/s11689-020-09325-2
  • Peer Reviewed / Open Access
• [Journal Article] Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder (2020)
  • Author(s): Kato Hidekazu、Kushima Itaru、Mori Daisuke、Yoshimi Akira、Aleksic Branko、Nawa Yoshihiro、Toyama Miho、Furuta Sho、Yu Yanjie、Ishizuka Kanako、Kimura Hiroki、Arioka Yuko、Tsujimura Keita、Morikawa Mako、Okada Takashi、Inada Toshiya、Nakatochi Masahiro、Shinjo Keiko、Kondo Yutaka、Kaibuchi Kozo、Egawa Jun et al
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 421-421
  • DOI: 10.1038/s41398-020-01107-7
  • Peer Reviewed / Open Access
• [Journal Article] Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia (2020)
  • Author(s): Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki
  • Journal Title: Psychiatry and clinical neurosciences Volume: 1 Issue: 5 Pages: 1-10
  • DOI: 10.1111/pcn.12993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk (2020)
  • Author(s): Mariko Sekiguchi, Akiko Kodama,... Emiko Shishido,... Daisuke Mori, Norio Ozaki
  • Journal Title: Translational psychiatry Volume: 10 Issue: 1 Pages: 1-15
  • DOI: 10.1038/s41398-020-00917-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Implications of germline copy-number variations in psychiatric disorders: review of large-scale genetic studies (2020)
  • Author(s): Nakatochi Masahiro,Kushima Itaru,Ozaki Norio
  • Journal Title: Journal of Human Genetics Volume: 66 Issue: 1 Pages: 25-37
  • DOI: 10.1038/s10038-020-00838-1
  • Peer Reviewed
• [Journal Article] Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome. (2019)
  • Author(s): Baba M, Yokoyama K, Seiriki K, Naka Y, Matsumura K, Kondo M, Yamamoto K, Hayashida M, Kasai A, Ago Y, Nagayasu K, Hayata-Takano A, Takahashi A, Yamaguchi S, Mori D, Ozaki N, Yamamoto T, Takuma K, Hashimoto R, Hashimoto H, Nakazawa T.
  • Journal Title: Neuropsychopharmacology Volume: 44(12) Issue: 12 Pages: 2125-2135
  • DOI: 10.1038/s41386-019-0441-5
  • NAID: 130007811380
  • Peer Reviewed / Open Access
• [Journal Article] Proteomic analysis of lymphoblastoid cell lines from schizophrenic patients (2019)
  • Author(s): Yoshimi A, Yamada S, Kunimoto S, Aleksic B, Hirakawa A, Ohashi MS, Matsumoto A, Hada K, Itoh N, Arioka Y, Kimura H, Kushima I, Nakamura Y, Shiino T, Mori D, Tanaka S, Hamada S, Noda Y, Nagai T, Yamada K, Ozaki N
  • Journal Title: Translational Psychiatry Volume: 9 Issue: 1 Pages: 126-126
  • DOI: 10.1038/s41398-019-0461-2
  • Peer Reviewed / Open Access
• [Journal Article] Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility (2018)
  • Author(s): Yu Yanjie、Lin Yingni、Takasaki Yuto、Wang Chenyao、Kimura Hiroki、Xing Jingrui、Ishizuka Kanako、Toyama Miho、Kushima Itaru、Mori Daisuke、Arioka Yuko、Uno Yota、Shiino Tomoko、Nakamura Yukako、Okada Takashi、Morikawa Mako、Ikeda Masashi、Iwata Nakao、Okahisa Yuko、Takaki Manabu、Sakamoto Shinji、et al.
  • Journal Title: Translational Psychiatry Volume: 8 Issue: 1 Pages: 12-20
  • DOI: 10.1038/s41398-017-0061-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aberrant functional connectivity between the thalamus and visual cortex is related to attentional impairment in schizophrenia (2018)
  • Author(s): Yamamoto Maeri、Kushima Itaru、Suzuki Ryohei、Branko Aleksic、Kawano Naoko、Inada Toshiya、Iidaka Tetsuya、Ozaki Norio
  • Journal Title: Psychiatry Research: Neuroimaging Volume: 278 Pages: 35-41
  • DOI: 10.1016/j.pscychresns.2018.06.007
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability (2018)
  • Author(s): Kunisawa Kazuo、Shimizu Takeshi、Kushima Itaru、Aleksic Branko、Mori Daisuke、Osanai Yasuyuki、Kobayashi Kenta、Taylor Anna M.、Bhat Manzoor A.、Hayashi Akiko、Baba Hiroko、Ozaki Norio、Ikenaka Kazuhiro
  • Journal Title: Journal of Neurochemistry Volume: 147 Issue: 3 Pages: 395-408
  • DOI: 10.1111/jnc.14553
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induced pluripotent stem cells derived from a schizophrenia patient with ASTN2 deletion (2018)
  • Author(s): Arioka Yuko、Kushima Itaru、Kubo Hisako、Mori Daisuke、Ozaki Norio
  • Journal Title: Stem Cell Research Volume: 30 Pages: 81-84
  • DOI: 10.1016/j.scr.2018.05.013
• [Journal Article] Copy Number Variant in the Region of Adenosine Kinase (ADK) and Its Possible Contribution to Schizophrenia Susceptibility (2017)
  • Author(s): Kimura Hiroki、Kushima Itaru、Yohimi Akira、Aleksic Branko、Ozaki Norio
  • Journal Title: Int J Neuropsychopharmacol Volume: - Issue: 5 Pages: 1-5
  • DOI: 10.1093/ijnp/pyx103
  • Peer Reviewed
• [Presentation] ゲノム医療の現状と今後の方向性 (2020)
  • Author(s): 尾崎紀夫
  • Organizer: 日本医療薬学会年会
• [Presentation] 多施設共同研究とゲノム情報の集約により精神疾患の病態解明から根本的治療薬開発へ (2020)
  • Author(s): 尾崎紀夫
  • Organizer: in NPBPPP2020シンポジウム本邦における精神科領域の個別化医療技術開発とバイオバンキングの展望
• [Presentation] 自閉スペクトラム症ゲノム解析の現状 (2020)
  • Author(s): 尾崎紀夫
  • Organizer: 児童青年精神医学会:シンポジウム１「最新の自閉症学」
• [Presentation] 精神疾患のゲノム解析を起点とした病態解明から創薬へ (2020)
  • Author(s): 尾崎紀夫
  • Organizer: 日本人類遺伝学会・教育セッション
• [Presentation] 精神疾患患者由来ゲノム・iPS細胞・死後脳の情報整備による大規模解析から根本的治療薬創成へ (2019)
  • Author(s): 尾崎紀夫
  • Organizer: 精神神経学会研究推進委員会シンポジウム
• [Presentation] 22q11.2 deletion syndrome: clinical phenotypes to pathogenesis of mental disorders associated with this variant. (2019)
  • Author(s): Ozaki N
  • Organizer: The 59th Annual Meeting of the Japanese Teratology Society The 13th World Congress of International Cleft Lip and Palate Foundation CLEFT2019
  • Int'l Joint Research / Invited
• [Presentation] Drug development for schizophrenia based on the pathogenesis from rare disease-susceptibility variants. (2019)
  • Author(s): Ozaki N
  • Organizer: ASCNP2019DrugDevelopment
  • Int'l Joint Research