Development of a new translational medicine for epilepsy using the Pten-mutant mice

• Project/Area Number: 15K09624
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• 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): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: Pten / てんかん / 自閉症 / PI3-AKT-mTOR経路 / 治療 / 海馬 / ノックアウトマウス / Crh-POMC(ACTH) / Pomc / 分子経路 / PI3K-AKT-mTOR / Crh-ACTH軸 / AKT-mTOR / 海馬歯状回 / 皮質形成異常 / 神経分化 / mTOR / ラパマイシン

Outline of Final Research Achievements

In the present study, we have generated conditional knockout mice that lacked expression of Pten in the Pomc-expressing neurons in the developing brain. All of these mice started showing generalized seizures from 8-9 weeks of age and died by 11 weeks of age. Biochemical studies and microscopic observation detected the age-dependent hypertrophy and dysmorphic appearance of the hippocampal dentate gyrus. We have also found that excitatory-inhibitory and Crh-Pomc (ACTH) unbalances became prominent in the dentate gyrus before the onset of seizures. We confirmed that the treatment with rapamycin prevented the onset of seizures and premature death of Pten-mutant mice. These data provide evidence that PI3K-AKT-mTOR is a molecular pathway that can be a therapeutic target for intractable epilepsy in future medicine.

Research Products

• [Journal Article] Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome (2018)
  • Author(s): Hirofuji S, Hirofuji Y, Kato H, Masuda K, Yamaza H, Sato H, Takayama F, Torio M, Sakai Y,Ohga S, Taguchi T, Nonaka K
  • Journal Title: Biochem Biophys Res Commun Volume: 498 Pages: 898-904
  • Peer Reviewed
• [Journal Article] Effective shunt closure for pulmonary hypertension and liver dysfunction in congenital portosystemic venous shunt (2018)
  • Author(s): Uike Kiyoshi、Nagata Hazumu、Hirata Yuichiro、Yamamura Kenichiro、Terashi Eiko、Matsuura Toshiharu、Morihana Eiji、Ohkubo Kazuhiro、Ishii Kanako、Sakai Yasunari、Taguchi Tomoaki、Ohga Shouichi
  • Journal Title: Pediatric Pulmonology Volume: 53 Issue: 4 Pages: 505-511
  • DOI: 10.1002/ppul.23944
  • Peer Reviewed / Open Access
• [Journal Article] Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2 (2017)
  • Author(s): Akamine S、Sagata N、Sakai Y、Kato TA.、Nakahara T、Matsushita Y、Togao O、Hiwatashi A、Sanefuji M、Ishizaki Y、Torisu H、Saitsu H、Matsumoto N、Hara T、Sawa A、Kano S、Furue M、Kanba S、Shaw CA.、Ohga S
  • Journal Title: Epilepsia Open Volume: 3 Issue: 1 Pages: 81-85
  • DOI: 10.1002/epi4.12085
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sustained endocrine profiles of a girl with WAGR syndrome (2017)
  • Author(s): Takada Y, Sakai Y, Matsushita Y, Ohkubo, K, Koga Y, Akamine S, Torio M, Ishizaki Y, Sanefuji M, Torisu H, Shaw CA, Kagami M, Hara T, Ohga S
  • Journal Title: BMC Med Genet Volume: 18 Pages: 13905-13905
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulated gene expressions of MEX3D, FOS and BCL2 in human induced-neuronal (iN) cells from NF1 patients: a pilot study (2017)
  • Author(s): Sagata N, Kato TA, Kano S, Ohgidani M, Shimokawa N, Sato-Kasai M, Hayakawa K, Kuwano N, Wilson AM, Ishizuka K, Kato S, Nakahara T, Nakahara-Kido M, Setoyama D, Sakai Y, Ohga S, Furue M, Sawa A, Kanba S
  • Journal Title: Sci Rep Volume: 7 Pages: 13905-13905
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Calcineurin inhibitors exacerbate coronary arteritis via the MyD88 signaling pathway in a murine model of Kawasaki disease (2017)
  • Author(s): Murata K, Motomura Y, Tanaka T, Kanno S, Yano T, Onimaru M, himoyama A, Nishio H, Sakai Y, Oh-hora M, Hara H, Fukase K, Takada H, Masuda S, Ohga S, Yamasaki S, Hara T
  • Journal Title: Clin Exp Immunol Volume: 190 Pages: 54-67
  • Peer Reviewed
• [Journal Article] Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome (2017)
  • Author(s): Imagawa E, Higashimoto K, Sakai Y, Numakura C, Okamoto N, Matsunaga S, Ryo A, Sato Y, Sanefuji M, Ihara K, Takada Y, Nishimura G, Saitsu H, Mizuguchi T, Miyatake S, Nakashima M, Miyake N, Soejima H, Matsumoto N
  • Journal Title: Hum Mutat Volume: 38 Pages: 637-648
  • Peer Reviewed
• [Journal Article] Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome (2017)
  • Author(s): Eri Imagawa, Ken Higashimoto, Yasunari Sakai, Chikahiko Numakura, Nobuhiko Okamoto, Satoko Matsunaga, Akihide Ryo, Yoshinori Sato, Masafumi Sanefuji, Kenji Ihara, Yui Takada, Gen Nishimura, Hirotomo Saitsu, Takeshi Mizuguchi, Satoko Miyatake, Mitsuko Nakashima, Noriko Miyake, Hidenobu Soejima, Naomichi Matsumoto
  • Journal Title: Human Mutation Volume: 印刷中 Issue: 6 Pages: 637-648
  • DOI: 10.1002/humu.23200
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice. (2016)
  • Author(s): Matsushita Y, Sakai Y, Shimmura M, Shigeto H, Nishio M, Akamine S, Sanefuji M, Ishizaki Y, Torisu H, Nakabeppu Y, Suzuki A, Takada H, Hara T.
  • Journal Title: Sci Rep Volume: 未 Issue: 1 Pages: 22991-22991
  • DOI: 10.1038/srep22991
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Involuntary movements and coma as the prognostic marker for acute encephalopathy with biphasic seizures and late reduced diffusion (2016)
  • Author(s): Lee S, Sanefuji M, Torio M, Kaku N, Ichimiya Y, Mizuguchi S, Baba H, Sakai Y, Ishizaki Y, Torisu H, Kira R Hara T, Ohga S
  • Journal Title: J Neurol Sci Volume: 370 Pages: 39-43
  • DOI: 10.1016/j.jns.2016.09.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis (2016)
  • Author(s): Kanemasa H, Fukai R, Sakai Y, Torio M, Miyake N, Lee S, Ono H, Akamine S, Nishiyama K, Sanefuji M, Ishizaki Y, Torisu H, Saitsu H, Matsumoto N, Hara T
  • Journal Title: BMC Neurol Volume: 16 Issue: 1 Pages: 174-174
  • DOI: 10.1186/s12883-016-0680-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A nationwide survey of pediatric acquired demyelinating syndromes in Japan (2016)
  • Author(s): Yamaguchi Y, Torisu H, Kira R, Ishizaki Y, Sakai Y, Sanefuji M, Aiba H, Ichiyama T, Oka A, Kishi T, Kimura S, Kubota M, Takanashi J, Takahashi Y, Tamai H, Natsume J, Hamano S, Hirabayashi S, Maegaki Y, Mizuguchi M, Minagawa K, Yoshikawa H, Kira J, Kusunoki S, Takada H, Hara T
  • Journal Title: Neurology Volume: 87 Pages: 2006-2015
  • Peer Reviewed