A study for convergent molecular mechanisms underlying epileptic encephalopathy using cortical organoids

• Project/Area Number: 19K08281
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kyushu University
• Principal Investigator: Sakai Yasunari 九州大学, 医学研究院, 准教授 (10380396)
• Co-Investigator(Kenkyū-buntansha): 中別府 雄作 九州大学, 生体防御医学研究所, 教授 (30180350)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: GNAO1 / 発達性てんかん性脳症 / 分子シグナル / 細胞骨格 / SPTAN1 / タンパク質複合体 / 極性 / オルガノイド / iPS / 治療標的 / てんかん性脳症 / 治療モデル

Outline of Research at the Start

早期発症型てんかん性脳症(EOEE)は、乳児期早期に難治性てんかんを発症し、多くは長期的に重度の知的障害を伴う予後不良な疾患群である。本研究に先立ち、EOEE関連遺伝子にコードされたタンパク質が神経細胞内で構成する複合体を同定した。今回、EOEE患者由来iPS/皮質オルガノイドを用いて分子病態を再現し、新しい治療標的を見出すための基盤を構築する。研究期間内に、下記1-3を実現する。
1.EOEE関連タンパク質(GNAO1/CDKL5/TRIM8)複合体およびネットワークの構築
2.異なるEOEE関連分子間に存在する収束的シグナルの同定
3.皮質オルガノイドおよびマウスモデルの樹立

Outline of Final Research Achievements

Through a proteomic search for Gao, encoded by a developmental and epileptic encephalopathy (DEE)-associated gene GNAO1, we found that the two DEE-associated proteins, Gao and SPTAN1 formed an endogenous complex in the brain. GNAO1-mutated brain organoids showed aberrant expressions of SPTAN1 and other genes associated with axon initial segment and cytoskeletal remodeling. GNAO1 was thus suggested to regulate the process acquiring the functional polarity of differentiating neurons (Akamine S, FASEB J, 2020).

Academic Significance and Societal Importance of the Research Achievements

異なる二つのDEE関連遺伝子(GaoとSPTAN1)が脳内で複合体を形成し、神経分化に重要な役割を果たすことを初めて明らかにした。これらのタンパク質複合体が脳内で制御する下流分子シグナルをさらに明らかにすることで、難治性てんかんにおける新しい治療標的の同定に寄与できると考えた。

Research Products

• [Journal Article] Paroxysmal sympathetic hyperactivity and the later development of epilepsy in a chemotherapy-associated brain damage (2021)
  • Author(s): Taira Ryoji、Yamamura Kenichiro、Maeda Tomoko、Sakata Ayumi、Watanabe Eriko、Shimogawa Takafumi、Mukae Nobutaka、Ikeda Chizuru、Migita Masahiro、Watanabe Osamu、Koga Yuhki、Sakai Yasunari、Ohga Shouichi
  • Journal Title: Brain and Development Volume: 43 Issue: 10 Pages: 1044-1050
  • DOI: 10.1016/j.braindev.2021.07.001
  • Peer Reviewed
• [Journal Article] Translational pediatrics: clinical perspective for Phelan?McDermid syndrome and autism research (2021)
  • Author(s): Sakai Yasunari、Okuzono Sayaka、Schaaf Christian P.、Ohga Shouichi
  • Journal Title: Pediatric Research Volume: 91 Issue: 2 Pages: 00-00
  • DOI: 10.1038/s41390-021-01806-x
  • Peer Reviewed
• [Journal Article] Acute-phase electroencephalography for an infantile atypical teratoid/rhabdoid tumor (2021)
  • Author(s): Ichimiya Yuko、Mizuguchi Soichi、Motomura Yoshitomo、Koga Yuhki、Kaku Noriyuki、Hata Nobuhiro、Yoshimoto Koji、Sakata Ayumi、Suzuki Satoshi O.、Iwaki Toru、Sakai Yasunari、Ohga Shouichi
  • Journal Title: Clinical Neurology and Neurosurgery Volume: 209 Pages: 106922-106922
  • DOI: 10.1016/j.clineuro.2021.106922
• [Journal Article] Vitamin A deficiency?associated corneal perforation in a boy with autism spectrum disorder: A case report and literature review (2021)
  • Author(s): Adachi Shunichi、Torio Michiko、Okuzono Sayaka、Motomura Yoshitomo、Ichimiya Yuko、Sonoda Yuri、Nagata Jyunya、Okamoto Misato、Notomi Shoji、Sanefuji Masafumi、Sakai Yasunari、Ohga Shouichi
  • Journal Title: Nutrition Volume: 90 Pages: 111275-111275
  • DOI: 10.1016/j.nut.2021.111275
  • Peer Reviewed / Open Access
• [Journal Article] Favorable outcomes of interferon-α and ribavirin treatment for a male with subacute sclerosing panencephalitis (2021)
  • Author(s): Sonoda Yuri、Sonoda Motoshi、Yonemoto Kousuke、Sanefuji Masafumi、Taira Ryoji、Motomura Yoshitomo、Ishimura Masataka、Torisu Hiroyuki、Kira Ryutaro、Kusuhara Koichi、Sakai Yasunari、Ohga Shouichi
  • Journal Title: Journal of Neuroimmunology Volume: 358 Pages: 577656-577656
  • DOI: 10.1016/j.jneuroim.2021.577656
  • Peer Reviewed / Open Access
• [Journal Article] Impaired neurite development and mitochondrial dysfunction associated with calcium accumulation in dopaminergic neurons differentiated from the dental pulp stem cells of a patient with metatropic dysplasia (2021)
  • Author(s): Xiao Sun, Hiroki Kato, Hiroshi Sato, Michiko Torio, Xu Han, Yu Zhang, Yuta Hirofuji, Takahiro A. Kato, Yasunari Sakai, Shouichi Ohga, Satoshi Fukumoto, Keiji Masuda
  • Journal Title: Biochem Biophys Rep. Volume: 26 Pages: 00-00
  • DOI: 10.1016/j.bbrep.2021.100968
  • Peer Reviewed / Open Access
• [Journal Article] Predictive values of early head computed tomography for survival outcome after cardiac arrest in childhood: a pilot study (2021)
  • Author(s): Tetsuhara Kenichi、Kaku Noriyuki、Watanabe Yuka、Kumamoto Masaya、Ichimiya Yuko、Mizuguchi Soichi、Higashi Kanako、Matsuoka Wakato、Motomura Yoshitomo、Sanefuji Masafumi、Hiwatashi Akio、Sakai Yasunari、Ohga Shouichi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 12090-12090
  • DOI: 10.1038/s41598-021-91628-y
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of Pediatric Admissions for Kawasaki Disease or Infectious Disease During the COVID-19 State of Emergency in Japan (2021)
  • Author(s): Hara Takuya、Furuno Kenji、Yamamura Kenichiro、Kishimoto Junji、Mizuno Yumi、Murata Kenji、Onoyama Sagano、Hatae Ken、Takemoto Megumi、Ishizaki Yoshito、Kanno Shunsuke、Sato Kazuo、Motomura Yoshitomo、Sakai Yasunari、Ohga Shouichi、Yashiro Mayumi、Nakamura Yoshikazu、Hara Toshiro
  • Journal Title: JAMA Network Open Volume: 4 Issue: 4 Pages: e214475-e214475
  • DOI: 10.1001/jamanetworkopen.2021.4475
• [Journal Article] De novo ATP1A3 variants cause polymicrogyria (2021)
  • Author(s): Miyatake Satoko、Kato Mitsuhiro、Kumamoto Takuma、Hirose Tomonori、他
  • Journal Title: Science Advances Volume: 7 Issue: 13 Pages: 2368-2368
  • DOI: 10.1126/sciadv.abd2368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants (2021)
  • Author(s): Kobayashi Y
  • Journal Title: Brain and Development Volume: 43 Issue: 4 Pages: 505-514
  • DOI: 10.1016/j.braindev.2020.12.006
  • Peer Reviewed / Open Access
• [Journal Article] Neurodevelopmental outcomes of high-risk preterm infants: A prospective study in Japan (2020)
  • Author(s): Torio Michiko、Iwayama Mariko、Sawano Toru、Inoue Hirosuke、Ochiai Masayuki、Taira Ryoji、Yonemoto Kousuke、Ichimiya Yuko、Sonoda Yuri、Sasazuki Momoko、Ishizaki Yoshito、Sanefuji Masafumi、Yamane Kenichi、Yamashita Hiroshi、Torisu Hiroyuki、Kira Ryutaro、Hara Toshiro、Kanba Shigenobu、Sakai Yasunari、Ohga Shouichi
  • Journal Title: Neurology: Clinical Practice Volume: - Issue: 5 Pages: 398-405
  • DOI: 10.1212/cpj.0000000000000920
  • Peer Reviewed
• [Journal Article] GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons. (2020)
  • Author(s): Akamine S, Okuzono S, Yamamoto H, Setoyama D, Sagata N, Ohgidani M, Kato TA, Ishitani T, Kato H, Masuda K, Matsushita Y, Ono H, Ishizaki Y, Sanefuji M, Saitsu H, Matsumoto N, Kang D, Kanba S, Nakabeppu Y, Sakai Y, Ohga S.
  • Journal Title: FASEB J Volume: 34 Issue: 12 Pages: 16601-16621
  • DOI: 10.1096/fj.202001113r
  • Peer Reviewed / Open Access
• [Journal Article] De novo CACNA1G variants in developmental delay and early-onset epileptic encephalopathies (2020)
  • Author(s): Misako Kunii, Hiroshi Doi, Shunta Hashiguchi, Toyojiro Matsuishi, Yasunari Sakai, Mizue Iai, Masaki Okubo, Haruko Nakamura, Keita Takahashi, Atsuko Katsumoto, Mikiko Tada, Hideyuki Takeuchi, Taro Ishikawa, Noriko Miyake, Hirotomo Saitsu, Naomichi Matsumoto, Fumiaki Tanaka
  • Journal Title: Journal of the Neurological Sciences Volume: 416 Pages: 117047-117047
  • DOI: 10.1016/j.jns.2020.117047
  • Peer Reviewed / Open Access
• [Journal Article] Forskolin rapidly enhances neuron‐like morphological change of directly induced‐neuronal cells from neurofibromatosis type 1 patients (2020)
  • Author(s): Sagata N
  • Journal Title: Neuropsychopharmacology Reports Volume: 40 Issue: 4 Pages: 396-400
  • DOI: 10.1002/npr2.12144
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gastrointestinal symptoms as an extended clinical feature of Pierson syndrome: A case report and review of the literature (2020)
  • Author(s): Nishiyama K, Kurokawa M, Torio M, Sakai Y*, Arima M, Tsukamoto S, Obata S, Minamikawa S, Nozu K, Kaku N, Maehara Y, Sonoda KH, Taguchi T, Ohga S
  • Journal Title: BMC Med Genet Volume: NA Issue: 1
  • DOI: 10.1186/s12881-020-01019-9
  • Peer Reviewed / Open Access
• [Journal Article] The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S. (2020)
  • Author(s): Kurokawa M, Torio M, Ohkubo K, Tocan V, Ohyama N, Toda N, Ishii K, Nishiyama K, Mushimoto Y, Sakamoto R, Nakaza M, Horie R, Kubota T, Takahashi MP, Sakai Y, Nomura M, Ohga S.
  • Journal Title: Mol Genet Genomic Med Volume: - Issue: 4
  • DOI: 10.1002/mgg3.1175
  • Peer Reviewed / Open Access
• [Journal Article] Survival and Ocular Preservation in a Long-Term Cohort of Japanese Patients With Retinoblastoma. (2020)
  • Author(s): Ueda T , Koga Y , Yoshikawa H, Tanabe M, Yamana K, Oba Y, Nakashima K, Ono H, Ichimura T, Hasegawa S, Kato W, Kobayashi T, Nakayama H,Sakai Y, Yoshitake T, Ohga S, Oda Y, Suzuki S, Sonoda K, Ohga S.
  • Journal Title: BMC Pediatr Volume: 20 Issue: 1 Pages: 37-37
  • DOI: 10.1186/s12887-020-1923-7
  • Peer Reviewed / Open Access
• [Journal Article] De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage: A case report and review of the literature. (2020)
  • Author(s): Kinoshita K, Ishizaki Y, Yamamoto H, Sonoda M, Yonemoto K, Kira R, Sanefuji M, Ueda A, Matsui H, Ando Y, Sakai Y, Ohga S.
  • Journal Title: Eur J Med Genet Volume: 63 Issue: 4 Pages: 103825-103825
  • DOI: 10.1016/j.ejmg.2019.103825
  • Peer Reviewed
• [Journal Article] Lipidomics links oxidized phosphatidylcholines and coronary arteritis in Kawasaki disease (2019)
  • Author(s): Nakashima Y, Sakai Y, Mizuno Y, Furuno K, Hirono K, Takatsuki S, Suzuki H, Onouchi Y, Kobayashi T, Tanabe K, Hamase K, Miyamoto T, Aoyagi R, Arita M, Yamamura K, Tanaka T, Nishio H, Takada H, Ohga S, Hara T.
  • Journal Title: Cardiovascular Research Volume: - Issue: 1 Pages: 0-0
  • DOI: 10.1093/cvr/cvz305
  • Peer Reviewed / Open Access
• [Journal Article] Management of apnea in infants with trisomy 18. (2019)
  • Author(s): Taira R, Inoue H, Sawano T, Fujiyoshi J, Ichimiya Y, Torio M, Sanefuji M, Ochiai M, Sakai Y, Ohga S.
  • Journal Title: Dev Med Child Neurol Volume: in press Issue: 7 Pages: 119-125
  • DOI: 10.1111/dmcn.14403
  • Peer Reviewed
• [Journal Article] Prognostic factors for survival of herpes simplex virus-associated hemophagocytic lymphohistiocytosis (2019)
  • Author(s): Sonoda M, Ishimura M, Eguchi K, Shiraishi A, Kanno S, Kaku N, Inoue H, Motomura Y, Ochiai M, Sakai Y, Nakayama M, Ohara O, Ohga S
  • Journal Title: Int J Hematol Volume: NA Issue: 1 Pages: 131-136
  • DOI: 10.1007/s12185-019-02738-3
  • Peer Reviewed
• [Journal Article] Association of perinatal factors of epilepsy in very low birth weight infants, using a nationwide database in Japan (2019)
  • Author(s): Matsushita Yuki、on behalf of the Neonatal Research Network of Japan (NRNJ)、Sakai Yasunari、Torio Michiko、Inoue Hirosuke、Ochiai Masayuki、Yasuoka Kazuaki、Kurata Hiroaki、Fujiyoshi Junko、Ichiyama Masako、Taguchi Tomoaki、Kato Kiyoko、Ohga Shouichi
  • Journal Title: Journal of Perinatology Volume: 39 Issue: 11 Pages: 1472-1479
  • DOI: 10.1038/s41372-019-0494-7
  • Peer Reviewed
• [Journal Article] Decision-making dilemmas of paediatricians: a qualitative study in Japan. (2019)
  • Author(s): Sasazuki M, Sakai Y, Kira R, Toda N, Ichimiya Y, Akamine S, Torio M, Ishizaki Y, Sanefuji M, Narama M, Itai K, Hara T, Takada H, Kizawa Y, Ohga S.
  • Journal Title: BMJ Open Volume: 9 Issue: 8 Pages: e026579-e026579
  • DOI: 10.1136/bmjopen-2018-026579
  • Peer Reviewed / Open Access
• [Journal Article] Late-Onset Circulatory Collapse and Risk of Cerebral Palsy in Extremely Preterm Infants (2019)
  • Author(s): Yasuoka Kazuaki、Inoue Hirosuke、Egami Naoki、Ochiai Masayuki、Tanaka Koichi、Sawano Toru、Kurata Hiroaki、Ichiyama Masako、Fujiyoshi Junko、Matsushita Yuki、Sakai Yasunari、Ohga Shouichi
  • Journal Title: The Journal of Pediatrics Volume: 212 Pages: 117-123.e4
  • DOI: 10.1016/j.jpeds.2019.05.033
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy (2019)
  • Author(s): Takata Atsushi、Nakashima Mitsuko、Saitsu Hirotomo、Osaka Hitoshi、Nakamura Kazuyuki、Takeshita Saoko、Sakai Yasunari、Miyake Noriko、Miyatake Satoko、Matsumoto Naomichi
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 2506-2506
  • DOI: 10.1038/s41467-019-10482-9
  • Peer Reviewed / Open Access
• [Journal Article] Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder (2019)
  • Author(s): Nguyen Nguyen Huong Thi、Kato Hiroki、Sato Hiroshi、Yamaza Haruyoshi、Sakai Yasunari、Ohga Shouichi、Nonaka Kazuaki、Masuda Keiji
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 513 Issue: 4 Pages: 1048-1054
  • DOI: 10.1016/j.bbrc.2019.04.084
  • Peer Reviewed
• [Journal Article] Recurrent de novo MAPK8IP3 variants cause neurological phenotypes (2019)
  • Author(s): Iwasawa Shinya、Yanagi Kumiko、Kikuchi Atsuo、Kobayashi Yasuko、Haginoya Kazuhiro、Matsumoto Hiroshi、Kurosawa Kenji、Ochiai Masayuki、Sakai Yasunari、Fujita Atsushi、Miyake Noriko、Niihori Tetsuya、ら
  • Journal Title: Annals of Neurology Volume: － Issue: 6 Pages: 927-933
  • DOI: 10.1002/ana.25481
  • Peer Reviewed
• [Journal Article] Late-onset sepsis and encephalopathy after bicycle-spoke injury: a case report (2019)
  • Author(s): Takemoto Ryuichi、Motomura Yoshitomo、Kaku Noriyuki、Ichimiya Yuko、Muraoka Mamoru、Kanno Shunsuke、Tanaka Tamami、Sakai Yasunari、Maehara Yoshihiko、Ohga Shouichi
  • Journal Title: BMC Infectious Diseases Volume: 19 Issue: 1 Pages: 472-472
  • DOI: 10.1186/s12879-019-4082-4
  • Peer Reviewed / Open Access
• [Journal Article] An acute encephalopathy with reduced diffusion in BRAF-associated cardio-facio-cutaneous syndrome (2019)
  • Author(s): Okuzono Sayaka、Fukai Ryoko、Noda Marie、Miyake Noriko、Lee Sooyoung、Kaku Noriyuki、Sanefuji Masafumi、Akamine Satoshi、Kanno Shunsuke、Ishizaki Yoshito、Torisu Hiroyuki、Kira Ryutaro、Matsumoto Naomichi、Sakai Yasunari、Ohga Shouichi
  • Journal Title: Brain and Development Volume: 41 Issue: 4 Pages: 378-381
  • DOI: 10.1016/j.braindev.2018.10.012
  • Peer Reviewed
• [Journal Article] A Child with Prostaglandin I₂-associated Thyrotoxicosis: Case Report (2019)
  • Author(s): Sonoda Yuri、Yamamura Kenichiro、Ishii Kanako、Ohkubo Kazuhiro、Ihara Kenji、Sakai Yasunari、Ohga Shouichi
  • Journal Title: Journal of Clinical Research in Pediatric Endocrinology Volume: 11 Issue: 2 Pages: 207-210
  • DOI: 10.4274/jcrpe.galenos.2018.2018.0169
  • Peer Reviewed / Open Access