Translational study of molecular pathogenesis on dystonia and developing its novel therapeutic interventions

• Project/Area Number: 21390269
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokushima
• Principal Investigator: KAJI Ryuji 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (00214304)
• Co-Investigator(Kenkyū-buntansha): GOTO Satoshi 徳島大学, 病院, 講師 (50240916) ; ASANUMA Koutaro 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 講師 (80448323)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2011: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2010: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2009: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 臨床神経生理学 / 神経科学 / 脳神経疾患 / 遺伝子 / ゲノム / 国際協力 / ジストニア / DYT3 / PET

Research Abstract

Dystonia is about one fourth as frequent as parkinsonism, and is not a rare disorder. It incapacitates sufferers to be bed-ridden if advanced. We for the first time found the gene(TAF-1) causing a hereditary dystonia DYT3, which is now being reported in Japan. It is therefore important to search for its pathogenesis and therapy. We previously found selective loss of neurons in striosome in the striatum of the basal ganglia in DYT3 autopsied brains. In this research, we found that NTAF-1, a neuron-specific isoform of TAF-1 is mainly localized in the striosome, which links the molecular pathogenesis with pathological and clinical findings.
We also reported clinical usefulness of zolpidem for treating dystonia in general. We developed a screening test for DYT3 dystonia, and tried a surgical treatment on a DYT3 patient with excellent outcomes.

Research Products

• [Journal Article] Efficacy of zolpidem for dystonia : a study among different subtypes (2012)
  • Author(s): Miyazaki Y, Sako W, Asanuma K, Izumi Y, Miki T, Kaji R.
  • Journal Title: Frontiers in neurology Volume: 3 Pages: 58-58
  • NAID: 120006869520
  • Peer Reviewed
• [Journal Article] Reduced serum ceruloplasmin levels in cervical dystonia (2012)
  • Author(s): Mezaki T, Kaji R.
  • Journal Title: European neurology Volume: 67 Pages: 256-256
  • Peer Reviewed
• [Journal Article] Cell type-specific localization of optineurin in the striatal neurons of mice : implications for neuronal vulnerability in Huntington' s disease (2012)
  • Author(s): Okita S, Morigaki R, Koizumi H, Kaji R, Nagahiro S, Goto S.
  • Journal Title: Neuroscience Volume: 202 Pages: 363-370
  • Peer Reviewed
• [Journal Article] Parkin interacts with Klokin1 for mitochondrial import and maintenance of membrane potential (2012)
  • Author(s): Kuroda Y, Sako W, Goto S, Kaji R et al.
  • Journal Title: Human molecular genetics Volume: 21 Pages: 991-1003
  • Peer Reviewed
• [Journal Article] Type A1 but not type A2 botulinum toxin decreases the grip strength of the contralateral foreleg through axonal transport from the toxin-treated foreleg of rats (2011)
  • Author(s): Torii Y, Akaike N, Harakawa T, Kaji R et al.
  • Journal Title: Journal of pharmacological sciences Volume: 117 Pages: 275-285
  • NAID: 10030453790
  • Peer Reviewed
• [Journal Article] New and emerging indications of botulinum toxin therapy (2011)
  • Author(s): Kaji R.
  • Journal Title: Parkinsonism & related disorders Volume: 17
  • Peer Reviewed
• [Journal Article] Practical management of botulinum toxin therapy (2011)
  • Author(s): Lim EC, Bhidayasiri R, Rosales RL, Kaji R.
  • Journal Title: Introduction. Parkinsonism & related disorders Volume: 17 Issue: 2 Pages: 123-5
  • DOI: 10.1016/j.parkreldis.2010.11.013
  • Peer Reviewed
• [Journal Article] Identification and localization of a neuron-specific isoform of TAF1 in rat brain : implications for neuropathology of DYT3 dystonia (2011)
  • Author(s): Sako W, Morigaki R, Kaji R, et al.
  • Journal Title: Neuroscience Volume: 189 Pages: 100-107
  • DOI: 10.1016/j.neuroscience.2011.05.031
  • Peer Reviewed
• [Journal Article] Bilateral pallidal deep brain stimulation in primary Meige syndrome (2011)
  • Author(s): Sako W, Morigaki R, Mizobuchi Y, Kaji R et al.
  • Journal Title: Parkinsonism & related disorders Volume: 17 Pages: 123-125
  • Peer Reviewed
• [Journal Article] Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy (2011)
  • Author(s): Taniguchi-Ikeda M, Kobayashi K, Kanagawa M, Yu CC, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, DiMauro S, Kaji R, Yokota T, Takeda S, Toda T
  • Journal Title: Nature Volume: 478 Issue: 7367 Pages: 127-131
  • DOI: 10.1038/nature10456
  • Peer Reviewed
• [Journal Article] The UCHL1 S18Y polymorphism and Parkinson's disease in a Japanese population. (2011)
  • Author(s): Snapinn KW, Larson EB, Kawakami H, Ujike H, Borenstein AR, Izumi Y, Kaji R, Maruyama H, Mata IF, Morino H, Oda M, Tsuang DW, Yearout D, Edwards KL, Zabetian CP.
  • Journal Title: Parkinsonism Relat Disord Volume: 21(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Temporal evolution of sporadic Creutzfeldt-Jakob disease monitored by 3-Tesla MR spectroscopy. (2011)
  • Author(s): Fujita K, Harada M, Yuasa T, Sasaki M, Izumi Y, Kaji R.
  • Journal Title: J Neurol Volume: 17(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Mutations of optineurin in amyotrophic lateral sclerosis (2010)
  • Author(s): Maruyama H, Morino H, Ito H, . Kaji R, Kawakami H.
  • Journal Title: Nature Volume: 465 Pages: 223-226
  • Peer Reviewed
• [Journal Article] Olfactory type G-protein alpha subunit in striosome-matrix dopamine systems in adult mice (2010)
  • Author(s): Sako W, Morigaki R, Nagahiro S, Kaji R, Goto S.
  • Journal Title: Neuroscience Volume: 170 Pages: 497-502
  • Peer Reviewed
• [Journal Article] Bilateral pallidal deep brain stimulation in primary Meige syndrome. (2010)
  • Author(s): Sako W, Morigaki R, Mizobuchi Y, Tsuzuki T, Ima H, Ushio Y, Nagahiro S, Kaji R, Goto S.
  • Journal Title: Parkinsonism Relat Disord Volume: 17 Pages: 123-5
  • Peer Reviewed
• [Journal Article] Comparison of effects of botulinum toxin subtype A1 and A2 using twitch tension assay and rat grip strength test. (2010)
  • Author(s): Torii Y, Kiyota N, Sugimoto N, Mori Y, Goto Y, Harakawa T, Nakahira S, Kaji R, Kozaki S, Ginnaga A.
  • Journal Title: Toxicon Volume: 57 Pages: 93-9
  • Peer Reviewed
• [Journal Article] Effects of A2 type botulinum toxin on spontaneous miniature and evoked transmitter release from the rat spinal excitatory and inhibitory synapses. (2010)
  • Author(s): Akaike N, Ito Y, Shin MC, Nonaka K, Torii Y, Harakawa T, Ginnaga A, Kozaki S, Kaji R.
  • Journal Title: Toxicon Volume: 56 Pages: 1315-26
  • Peer Reviewed
• [Journal Article] Olfactory type G-protein alpha subunit in striosome-matrix dopamine systems in adult mice. (2010)
  • Author(s): Sako W, Morigaki R, Nagahiro S, Kaji R, Goto S.
  • Journal Title: Neuroscience Volume: 13 Pages: 497-502
  • Peer Reviewed
• [Journal Article] Entrapment neuropathy and beyond. (2010)
  • Author(s): Kaji R.
  • Journal Title: J Physiol Volume: 1
  • Peer Reviewed
• [Journal Article] Long-term suppression of Meige syndrome after pallidal stimulation : a 10-year follow-up study (2010)
  • Author(s): Inoue N, Nagahiro S, Kaji R, Goto S.
  • Journal Title: Mov Disord Volume: 15 Pages: 1756-8
  • Peer Reviewed
• [Journal Article] GSK1358820 Spasticity Study Group. Botulinum toxin type A in post-stroke upper limb spasticity. (2010)
  • Author(s): Kaji R, Osako Y, Suyama K, Maeda T, Uechi Y, Iwasaki M
  • Journal Title: Curr Med Res Opin Volume: 26 Pages: 1983-92
  • Peer Reviewed
• [Journal Article] Mutations of optineurin in amyotrophic lateral sclerosis. (2010)
  • Author(s): Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H.
  • Journal Title: Nature Volume: 13 Pages: 223-6
  • Peer Reviewed
• [Journal Article] Botulinum toxin type A in post-stroke lower limb spasticity : a multicenter, double-blind, placebo-controlled trial. (2010)
  • Author(s): Kaji R, Osako Y, Suyama K, Maeda T, Uechi Y, Iwasaki M
  • Journal Title: J Neurol Volume: 257 Pages: 1330-7
  • Peer Reviewed
• [Journal Article] LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease. (2009)
  • Author(s): Zabetian CP, Yamamoto M, Lopez AN, Ujike H, Mata IF, Izumi Y, Kaji R, Maruyama H, Morino H, Oda M, Hutter CM, Edwards KL, Schellenberg GD, Tsuang DW, Yearout D, Larson EB, Kawakami H.
  • Journal Title: Mov Disord 24 Pages: 1034-1041
  • Peer Reviewed
• [Journal Article] Subthalamic nucleus deep brain stimulation for camptocormia associated with Parkinson's disease. (2009)
  • Author(s): Sako W, Nishio M, Maruo T, Shimazu H, Matsuzaki K, Tamura T, Mure H, Ushio Y, Nagahiro S, Kaji R, Goto S.
  • Journal Title: Mov Disord 24 Pages: 1076-1079
  • NAID: 10024369634
  • Peer Reviewed
• [Journal Article] uantitative determination of the biological activity of botulinum toxin type A by measuring the compound muscle action potential (CMAP) in rats. (2009)
  • Author(s): Sakamoto T, Torii Y, Takahashi M, Ishida S, Goto Y, Nakano H, Harakawa T, Ginnaga A, Kozaki S, Kaji R.
  • Journal Title: Toxicon 54 Pages: 857-861
  • Peer Reviewed
• [Journal Article] Long-term suppression of tremor by deep brain stimulation of the ventral intermediate nucleus of the thalamus combined with pallidotomy in hemiparkinsonian patients. (2009)
  • Author(s): Nishio M, Korematsu K, Yoshioka S, Nagai Y, Maruo, T, Ushio Y, Kaji R, Goto S.
  • Journal Title: J Clin Neurosci 16 Pages: 1489-1491
  • Peer Reviewed
• [Journal Article] Screening for TARDBP mutations in Japanese familial amyotrophic lateral sclerosis (2009)
  • Author(s): Kamada M, Maruyama H, Tanaka E, Morino H, Wate R, Ito H, Kusaka H, Kawano Y, Miki T, Nodera H, Izumi Y, Kaji R, Kawakami H.
  • Journal Title: J Neurol Sci 284 Pages: 69-71
  • NAID: 120001898369
  • Peer Reviewed
• [Presentation] Neuropathology update Lessons from DYT3 and other dystonias (2011)
  • Author(s): Kaji R
  • Organizer: 5th INTERNATIONAL DYSTONIA SYMPOSIUM BARCELONA
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2011-10-20
• [Presentation] Neuropathology update : Lessons from DYT3 and other dystonias (2011)
  • Author(s): Kaji R
  • Organizer: 5th INTERNATIONAL DYSTONIA SYMPOSIUM BARCELONA
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2011-10-20
• [Presentation] Japanese study experience sharing Upper limb study(BTX108509) (2010)
  • Author(s): Kaji R
  • Organizer: Lower limb study(BTX108512) Injection Training for the Study to Evaluate the Efficacy and Safety in Chinese Patients with Post-Stroke Upper Limb Spasticity
  • Place of Presentation: Building, China
  • Year and Date: 2010-03-13
• [Presentation] Japanese study experience sharing Upper limb study(BTX108509)/Lower limb study(BTX108512) (2010)
  • Author(s): 梶龍兒
  • Organizer: Injection Training for the Study to Evaluate the Efficacy and Safety in Chinese Patients with Post-Stroke Upper Limb Spasticity
  • Place of Presentation: 中国 上海The Headquarters Building No168 Tibet Road(M)
  • Year and Date: 2010-03-13
• [Presentation] Multifocal Motor neuropathy : Prof Bostock's contribution to clarify its pathophysiology (2009)
  • Author(s): 梶龍兒
  • Organizer: Festschrift in honour of Prof. Hugh Bostok, FRS
  • Place of Presentation: イギリス ロンドンBasement Lecture Theatre
  • Year and Date: 2009-11-06
• [Presentation] Molecular dissection of dystonia (2009)
  • Author(s): Kaji R
  • Organizer: 19^<th> World Congress of Neurology
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2009-10-29
• [Presentation] Molecular dissection of dystonia (2009)
  • Author(s): 梶龍兒
  • Organizer: 19th World Congress of Neurology
  • Place of Presentation: タイ バンコクThe Bang kok International Trade & Exhibition Centre
  • Year and Date: 2009-10-29
• [Presentation] Dopa-responsive dystonias : An update MDS (2009)
  • Author(s): Kaji R
  • Organizer: 13th International Congress
  • Place of Presentation: Paris, France
  • Year and Date: 2009-06-11
• [Presentation] Dopa-responsive dystonias : An update (2009)
  • Author(s): 梶龍兒
  • Organizer: MDS 13th International Congress
  • Place of Presentation: フランス パリLe Palais Des Congres de Paris
  • Year and Date: 2009-06-11
• [Presentation] Multifocal Motor Neuropathy (2009)
  • Author(s): 梶龍兒
  • Organizer: Neuromuscular Symposium in Honor of Austin J.Sumner, M.D
  • Place of Presentation: アメリカ ニューオーリンズLousiana State University Health Sciencea Center Mediacl Eduaction Building
  • Year and Date: 2009-05-08
• [Presentation] Therapeutic approach to spasticity : an update (2009)
  • Author(s): 梶龍兒
  • Organizer: 2009 Asian and Oceanian Congress on Clinical Neurophysiology
  • Place of Presentation: 韓国 ソウルSheraton Grand Walkerhill Hotel
  • Year and Date: 2009-04-16
• [Presentation] Pathophysiology of dystonia 2009 Spring KMDS Sympo (2009)
  • Author(s): Kaji R
  • Place of Presentation: Soul South Korea
  • Year and Date: 2009-04-11
• [Presentation] Pathophysiology of dystonia (2009)
  • Author(s): 梶龍兒
  • Organizer: 2009 Spring KMDS Sympo
  • Place of Presentation: 韓国 ソウルGrand Hyatt Hotel
  • Year and Date: 2009-04-11
• [Book] ボツリヌス療法アトラス (2012)
  • Author(s): 梶龍兒
  • Publisher: 医学書院
• [Book] ジストニア診療とケアマニュアル (2012)
  • Author(s): 堀内正浩・梶龍兒
  • Total Pages: 48
  • Publisher: 診断と治療社
• [Book] ジストニア診療とケアマニュアル (2011)
  • Author(s): 堀内正浩、梶龍兒
  • Publisher: 診断と治療社