Clarification of the link between nuclear import of neurodegenerative disease-causing proteins and the pathomechanisms

• Project/Area Number: 19591002
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nara Medical University
• Principal Investigator: HIRANO Makito Nara Medical University, 医学部, 准教授 (50347548)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 臨床神経分子遺伝学 / アラジン / アプラタキシン / XRCC1 / 核内輸送

Research Abstract

本研究の目的は種々の神経変性疾患原因蛋白の核内輸送に関して、運動ニューロン病様Triple A症候群(AAAS)の原因である核膜孔蛋白アラジンに依存性であるかを検討し、本疾患で障害を受けやすい古典的な核局在シグナル(NLS)以外の輸送シグナル同定と輸送機序の解明である。本研究により小脳失調原因蛋白アプラタキシンのみAAASの輸送障害を受け、他の原因蛋白は障害を受けないことが判明した。また、核内輸送障害を受けないDNA修復蛋白であるXRCC1において、輸送障害を改善するために重要なのは、古典的NLS(239-266残基)の下流267-276残基であることを同定した。この部位を含む新規NLS(239-276残基)38アミノ酸配列をminimum essential sequence of stretched nuclear localization signal(mstNLS)と名付けた。mstNLSを融合すると、輸送障害を受けていた小脳失調原因蛋白アプラタキシンはAAAS患者細胞の核内に効率よく輸送された。さらに、mstNLSは酸化ストレス下の正常細胞においても、強力な核局在シグナルとなることが証明された。以上から本研究成果は、AAASの病態機序改善のみならず、核内輸送研究に貢献しうると考えられる。

Research Products

• [Journal Article] Treatable fluctuating mental impairment in a patient with Bardet-Biedl syndrome (2009)
  • Author(s): Tonomura Y, Hirano M, Shimada K, Asai H, Ikeda M, Kataoka H, Tanaka I, Konishi N, Ueno S.
  • Journal Title: Clin Neurol Neurosurg 111 Pages: 102-104
  • Peer Reviewed
• [Journal Article] Cerebrospinal fluid-orexin levels and sleep attacks in four patients with Parkinson's disease (2009)
  • Author(s): Asai H, Hirano M, Furiya Y, Udaka F, Morikawa M, Kanbayashi T, Shimizu T, Ueno S.
  • Journal Title: Clin Neurol Neurosurg 111 Pages: 341-344
  • Peer Reviewed
• [Journal Article] Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach (2008)
  • Author(s): Deng H-X, Jiang H, Fu R, Zhai H, Shi Y, Liu E, Hirano M, C. Dal Canto M, Siddique T.
  • Journal Title: Hum Mol Genet 17 Pages: 2310-2319
  • Peer Reviewed
• [Journal Article] Comparative study of nucleotide excision repair defects between XPD-mutated fibroblasts derived from trichothiodystrophy and xeroderma pigmentosum patients (2008)
  • Author(s): Nishiwaki T, Kobayashi N, Iwamoto T, Yamamoto A, Sugiura S, Liu YC, Sarasin A, Okahashi Y, Hirano M, Ueno S, Mori T.
  • Journal Title: DNA Repair (Amst) 7 Pages: 1990-1998
  • Peer Reviewed
• [Journal Article] Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress (2008)
  • Author(s): Kiriyame T, Hirano M, Asai H, Ikeda M, Furiya Y, Ueno S.
  • Journal Title: Biochem Biophys Res Commun 374 Pages: 631-634
  • Peer Reviewed
• [Journal Article] Fixed epiglottis associated with subthalamic nucleus stimulation in Parkinson's disease (2008)
  • Author(s): Yanase M, Kataoka H, Kawahara M, Hirabayashi H, Yamanaka T, Hirano M, Ueno S.
  • Journal Title: J Neurol Neurosurg Psychiatry 79 Pages: 332-333
  • NAID: 10024369564
  • Peer Reviewed
• [Journal Article] Complete recovery of an aged patient with Guillain-Barre syndrome associated with multiple IgM anti-ganglioside antibodies (2008)
  • Author(s): Furiya Y, Hirano M, Kusunoki S, Ueda M, Sugie K, Nishiwaki T, Ueno S.
  • Journal Title: Muscle Nerve 38 Pages: 1630-1633
  • Peer Reviewed
• [Journal Article] Restoration of nuclear-import failure caused by triple A syndrome and oxidative stress. (2008)
  • Author(s): Kiriyama T, et al.
  • Journal Title: Biochem Biophys Res Commnun 374 Pages: 631-634
  • Peer Reviewed
• [Journal Article] Comparative study of nucleotide excision repair defects between XPD-mutated fibroblasts derived from trichothiodystrophy and xeroderma pigmentosum patients. (2008)
  • Author(s): Nishiwaki T, et al.
  • Journal Title: DNA repair 7 Pages: 1990-1998
  • Peer Reviewed
• [Journal Article] Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach (2008)
  • Author(s): Deng H-X, et al.
  • Journal Title: Hum Mol Genet 17 Pages: 2310-2319
  • Peer Reviewed
• [Journal Article] Identification of nuclear localization signal of XRCC1 overcoming impaired nuclear import in triple A syndrome. (2008)
  • Author(s): Kiriyama T, et al.
  • Journal Title: Ann Neurol 64
  • Peer Reviewed
• [Journal Article] Peripheral neuropathy in chromosome16q22.1-linked autosomal dominant cerebellar ataxia (2007)
  • Author(s): Furiya Y, Hirano M, Nomura M, Asai H, Kiriyama T, Ueno S.
  • Journal Title: J Neurol Neurosurg Psychiatry 78 Pages: 1009-1011
  • Peer Reviewed
• [Journal Article] Short half-lives of ataxia-associated aprataxin proteins in neuronal cells (2007)
  • Author(s): Hirano M, Asai H, Kiriyama T, Furiya Y, Iwamoto T, Nishiwaki T, Yamamoto A, Mori T, Ueno S.
  • Journal Title: Neurosci Lett 419 Pages: 184-187
  • Peer Reviewed
• [Journal Article] Diffusivity and diffusion anisotropy of cerebellar peduncles in cases of spinocerebe llar degenerative disease (2007)
  • Author(s): Taoka T, Kin T, Nakagawa H, Hirano M, Sakamoto M, Wada T, Takayama K, Wuttikul C, Iwasaki S, Ueno S, Kichikawa K.
  • Journal Title: Neuroimage 37 Pages: 387-393
  • Peer Reviewed
• [Journal Article] SPECT revealed cortical dysfunction in a patient who had genetically definite megalencephalic leukoencephalopathy with subcortical cysts (2007)
  • Author(s): Kiriyama T, Tanizawa E, Hirano M, Shinkai T, Asai H, Furiya Y, Ueno S.
  • Journal Title: Clin Neurol Neurosurg 109 Pages: 526-530
  • Peer Reviewed
• [Journal Article] Treatable fluctuating Parkinsonism and dementia in a patient with a dural arteriovenous fistula (2007)
  • Author(s): Kajitani M, Yagura H, Kawahara M, Hirano M, Ueno S, Fujimoto K, Sakaki T, Taoka T, Nakagawa H, Kichikawa K.
  • Journal Title: Mov Disord 22 Pages: 437-439
  • Peer Reviewed
• [Journal Article] Sympathetic disturbances increase risk of sudden cardiac arrest in sporadic ALS (2007)
  • Author(s): Asai H, Hirano M, Udaka F, Shimada K, Oda M, Kubori T, Nishinaka K, Tsujimura T, Izumi Y, Konishi N, Matsumoto S, Kameyama M, Ueno S.
  • Journal Title: J Neurol Sci 254 Pages: 78-83
  • Peer Reviewed
• [Journal Article] Short half-lives of ataxia-associated aprataxin proteins in neuronal cells (2007)
  • Author(s): Hirano M, et. al.
  • Journal Title: Neurosci Lett 419 Pages: 184-187
  • Peer Reviewed
• [Journal Article] Mutant ALADIN impairs selective nuclear import and DNA repair in triple Asyndrome (2007)
  • Author(s): Hirano M, et. al.
  • Journal Title: Ann Neurol 62
  • Peer Reviewed
• [Journal Article] 総説神経疾患と塩基除去修復
  • Author(s): 平野牧人, 森俊雄, 上野聡
  • Journal Title: 放射線生物研究 (印刷中)
  • Peer Reviewed
• [Journal Article] 総説神経疾患と塩基除去修復
  • Author(s): 平野牧人, 他2名
  • Journal Title: 放射線生物研究 (印刷中)
  • Peer Reviewed
• [Presentation] 酸化的DNA損傷修復系への小脳失調原因蛋白アプラタキシンの機能的関与 (2008)
  • Author(s): 平野牧人, 他7名
  • Organizer: 第48回放射線影響学会
  • Place of Presentation: 小倉
  • Year and Date: 2008-11-20
• [Presentation] In vivo DNA damage accumulation in aprataxin-related ataxia (2008)
  • Author(s): Hirano M, 他9名
  • Organizer: 134^<th> Annual meeting of American Neurological Association
  • Place of Presentation: Salt Lake City, USA
  • Year and Date: 2008-09-23
• [Presentation] In vivo DNA damage accumulation in aprataxin-related ataxia. (2008)
  • Author(s): Hirano M, 他9名
  • Organizer: 134^<th> Annual meeting of American Neurological Association
  • Place of Presentation: Salt Lake City, USA
  • Year and Date: 2008-09-23
• [Presentation] 眼球運動失行と低アルブミン血症を伴う早発型脊髄小脳失調症におけるDNA損傷の蓄積 (2008)
  • Author(s): 平野牧人, 他8名
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-16
• [Presentation] ALADINI482S causes hypersensitivity to oxidative stress by selective failure of DNA repair protein import in triple A syndrome (2007)
  • Author(s): 5. Asai H, Hirano M, 他5名
  • Organizer: Neuroscience
  • Place of Presentation: San Diego, USA
  • Year and Date: 2007-11-05
• [Presentation] ALADLNI482S causes hypersensitivily to oxidative stress by selective failure of DNA repair protein import in triple A syndrome (2007)
  • Author(s): Asai H, Hirano M, 他5名
  • Organizer: Neuroscience 2008
  • Place of Presentation: San Diego,USA
  • Year and Date: 2007-11-05
• [Presentation] A Japanese family with triple A syndrome caused by a novel mutation in the ALADIN gene (2007)
  • Author(s): Furiya Y, Hirano M, 他5名
  • Organizer: 5th Congress of the International Society for Autonomic Neuroscience
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2007-10-07
• [Presentation] A Japanese family with triple A syndrome caused by a novel mutation in the ALADIN gene (2007)
  • Author(s): Furiya Y, Hirano M, 他5名
  • Organizer: 5th Congress of the International Society for Autonomic Neuroscience
  • Place of Presentation: Kyoto,Japan
  • Year and Date: 2007-10-07
• [Presentation] Mutant ALADIN responsible for triple A syndrome impairs nuclear import of aprataxin, a DNA repair protein causative for ataxia (2007)
  • Author(s): Hirano M, 他5名
  • Organizer: Neuro2007(日本神経化学会総会)
  • Place of Presentation: 横浜
  • Year and Date: 2007-09-10
• [Presentation] Mutant ALADIN responsible for triple A syndrome impairs nuclear import of aprataxin,a DNA repair protein causative for ataxia (2007)
  • Author(s): Hirano M, 他5名
  • Organizer: Neuro2007(日本神経化学会総会)
  • Place of Presentation: 横浜
  • Year and Date: 2007-09-10
• [Presentation] 新たなALADIN遺伝子変異を伴うTriple A症候群における、小脳失調原因蛋白aprataxinの核内輸送障害 (2007)
  • Author(s): 浅井宏英、平野牧人, 他3名
  • Organizer: 第48回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-18
• [Presentation] 小脳失調原因蛋白aprataxin導入によるTriple A症候群のストレス起因性細胞死の抑制 (2007)
  • Author(s): 平野牧人, 他4名
  • Organizer: 第48回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-18
• [Presentation] 新たなALADIN遺伝子変異を伴うTriple A症候群における、小脳失調原因蛋白arataxinの核内輸送障害 (2007)
  • Author(s): 浅井 宏英、平野 牧人, 他3名
  • Organizer: 第48回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-18
• [Book] 医療の最先端-奈良医大からの発信- (2008)
  • Author(s): 平野牧人, 他42名
  • Total Pages: 208
  • Publisher: 創元社
• [Book] ケアマネジメント用語辞典 (2007)
  • Author(s): 平野牧人, 他101名
  • Total Pages: 545
  • Publisher: ミネルヴァ書房