A search for abnormal RNA metabolism in spinocerebellar ataxia type 31

• Project/Area Number: 24591252
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ISHIKAWA Kinya 東京医科歯科大学, 医学部附属病院, 教授 (30313240)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2012: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 遺伝子 / 脳 / 神経疾患 / ＲＮＡ / 脊髄小脳変性症 / ゲノム / マイクロアレー / 病態 / RNA

Outline of Final Research Achievements

We studied on human brain samples affected with spinocerebellar ataxia type 31 (SCA31). By expression analysis using microarray and RNA-seq, we found groups of genes which have meaningful alterations in their expression levels. Among those, we confirmed several genes that are down-regulated in SCA31 samples. Some of them were known to be involved in intracellular calcium homeostasis. We also found that SCA31 human Purkinje cells possess abnormal RNA structures called RNA foci which contain (UGGAA)n repeat, the transcript of (TGGAA)n repeat exclusively found in the SCA31 patients’ mutation locus. Such RNA foci were also found in cultured cells expressing SCA31 mutation constructs. These results suggest that the UGGAA repeat is involved in SCA31 pathogenesis.

Research Products

• [Journal Article] A novel mutation in ELOVL4 leading to spinocerebellar ataxia with the hot cross bun sign but lacking erythrokeratodermia: a broadened spectrum of SCA34. (2015)
  • Author(s): Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y, Majima T, Yamane K, Irioka T, Ishiura H, Doi K, Morishita S, Higashi M, Sekiguchi T, Koyama K, Ueda N, Miura Y, Miyatake S, Matsumoto N, Yokota T, Tanaka F, Tsuji S, Mizusawa H, Ishikawa K.
  • Journal Title: JAMA Neurology Volume: 6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Variants associated with Gaucher disease in multiple system atrophy. (2015)
  • Author(s): Mitsui J, Matsukawa T, Sasaki H, Yabe I, Nakahara Y, Momose Y, Takahashi Y, Hara K, Kakita A, Yamada M, Takahashi H, Onodera O, Nishizawa M, Watanabe H, Nakashima K, Ito H, Izumi Y, Kaji R, Kato T, Tsuji S, et al.
  • Journal Title: Ann Clin Transl Neurol. Volume: 2 Issue: 4 Pages: 417-426
  • DOI: 10.1002/acn3.185
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative evaluation of human cerebellum-dependent motor learning through prism adaptation of hand-reaching movement. (2015)
  • Author(s): Hashimoto Y, Honda T, Matsumura K, Nakao M, Soga K, Katano K, Yokota T, Mizusawa H, Nagao S, Ishikawa K
  • Journal Title: PLoS One. Volume: 10(3) Issue: 3 Pages: e0119376-e0119376
  • DOI: 10.1371/journal.pone.0119376
  • Peer Reviewed / Open Access
• [Journal Article] Rare frequency of downbeat positioning nystagmus in spinocerebellar ataxia type 31. (2015)
  • Author(s): Yabe I, Matsushima M, Yoshida K, Ishikawa K, Shirai S, Takahashi I, Sasaki H.
  • Journal Title: J Neurol Sci. Volume: Mar 15;350(1-2) Issue: 1-2 Pages: 90-92
  • DOI: 10.1016/j.jns.2014.12.042
  • NAID: 120005722547
  • Peer Reviewed / Open Access
• [Journal Article] CADASIL with a novel NOTCH3 mutation (Cys478Tyr). (2015)
  • Author(s): Ozaki K, Irioka T, Ishikawa K, Mizusawa H
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: Mar;24(3) Issue: 3 Pages: e61-e62
  • DOI: 10.1016/j.jstrokecerebrovasdis.2014.11.022
  • Peer Reviewed
• [Journal Article] Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion. (2014)
  • Author(s): Obayashi M, Stevanin G, Synofzik M, Monin ML, Duyckaerts C, Sato N, Streichenberger N, Vighetto A, Desestret V, Tesson C, Wichmann HE, Illig T, Huttenlocher J, Kita Y, Izumi Y, Mizusawa H, Schoels L, Klopstock T, Brice A, Ishikawa K, Duerr A
  • Journal Title: J Neurol Neurosurg Psychiatry. Volume: Dec 4 Issue: 9 Pages: 986-995
  • DOI: 10.1136/jnnp-2014-309153
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Relocation of p25α/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy. (2014)
  • Author(s): Ota K, Obayashi M, Ozaki K, Ichinose S, Kakita A, Tada M, Takahashi H, Ando N, Eishi Y, Mizusawa H, Ishikawa K.
  • Journal Title: Acta Neuropathol Commun Volume: Sep 11;2 Issue: 1 Pages: 136-136
  • DOI: 10.1186/s40478-014-0136-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The evaluation of polyglutamine repeats in autosomal dominant Parkinson's disease. (2014)
  • Author(s): Yamashita C, Tomiyama H, Funayama M, Inamizu S, Ando M, Li Y, Yoshino H, Araki T, Ichikawa T, Ehara Y, Ishikawa K, Mizusawa H, Hattori N.
  • Journal Title: Neurobiol Aging. Volume: 35 Issue: 7 Pages: 1779.e17-1779.e21
  • DOI: 10.1016/j.neurobiolaging.2014.01.022
  • Peer Reviewed / Open Access
• [Journal Article] Abnormal RNA structures (RNA foci) containing a penta-nucleotide repeat (UGGAA)n in the Purkinje cell nucleus is associated with spinocerebellar ataxia type 31 pathogenesis. (2013)
  • Author(s): Niimi Y, Takahashi M, Sugawara E, Umeda S, Obayashi M, Sato N, Ishiguro T, Higashi M, Eishi Y, Mizusawa H, Ishikawa K.
  • Journal Title: Neuropathology Volume: 33(6) Issue: 6 Pages: 600-611
  • DOI: 10.1111/neup.12032
  • Peer Reviewed
• [Journal Article] Cytoplasmic location of α1A voltage-gated calcium channel C-terminal fragment (Cav2.1-CTF) aggregate is sufficient to cause cell death. (2013)
  • Author(s): Takahashi M, Obayashi M, Ishiguro T, Sato N, Niimi Y, Ozaki K, Mogushi K, Mahmut Y, Tanaka H, Tsuruta F, Dolmetsch R, Yamada M, Takahashi H, Kato T, Mori O, Eishi Y, Mizusawa H, Ishikawa K.
  • Journal Title: PLoS ONE Volume: 8(3) Issue: 3 Pages: e50121-e50121
  • DOI: 10.1371/journal.pone.0050121
  • Peer Reviewed
• [Journal Article] Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6. (2012)
  • Author(s): Unno, T., Wakamori, M., Koike, M., Uchiyama, Y., Ishikawa, K., Kubota, H., Yoshida, T., Sasakawa, H., Peters, C., Mizusawa, H. and Watase K
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 109(43) Issue: 43 Pages: 17693-17698
  • DOI: 10.1073/pnas.1212786109
  • Peer Reviewed
• [Journal Article] Reduced brain-derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF-immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum (2012)
  • Author(s): Takahashi M, Ishikawa K, Sato N, Obayashi M, Niimi Y, Ishiguro T, Yamada M, Toyoshima Y, Takahashi H, Kato T, Takao M, Murayama M, Mori O, Eishi Y, Mizusawa H
  • Journal Title: Neuropathology Volume: (in press) Issue: 6 Pages: 593-603
  • DOI: 10.1111/j.1440-1789.2012.01302.x
  • Peer Reviewed
• [Journal Article] Prevalence of inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) deletion, the mutation for spinocerebellar ataxia type 15 (SCA15), in Japan screened by gene dosage (2012)
  • Author(s): Obayashi M, Ishikawa K, Izumi Y, Takahashi M, Niimi Y, Sato N, Onodera O, Kaji R, Nishizawa M, Mizusawa H
  • Journal Title: J Hum Genet Volume: 57(3) Issue: 3 Pages: 202-206
  • DOI: 10.1038/jhg.2012.5
  • Peer Reviewed
• [Presentation] Establishment of a novel system to apply cerebellar motor learning in clinics (2013)
  • Author(s): Kinya Ishikawa, Yuji Hashimoto, Takeru Honda, Soichi Nagao, and Hidehiro Mizusawa
  • Organizer: Gordon Research Conference, Cerebellum
  • Place of Presentation: New London, NH, USA
• [Presentation] A BAC transgenic mouse model of spinocerebellar ataxia type 31 (SCA31) exhibits RNA foci in Purkinje cells. (2013)
  • Author(s): Sato N, Ishikawa K, Niimi Y, Mizusawa H.
  • Organizer: The 65th Annual Meeting, The American Academy of Neurology.
  • Place of Presentation: San Diego Convention Center
• [Presentation] RNA mediated cell death is important in a cultured cell model of spinicerebellar ataxia type 31. (2012)
  • Author(s): Niimi Y, Ishikawa K, Sato N, Mizusawa H.
  • Organizer: The 2nd International Conference of Neural Tissue and Cell Culture.
  • Place of Presentation: 東京医科歯科大学
• [Presentation] A non-coding penta-nucleotide (UGGAA)n is essential for SCA31 pathogenesis. (2012)
  • Author(s): Ishikawa K.
  • Organizer: The 7th International Conference on Unstable Microsatellite and Human Disease.
  • Place of Presentation: Ste.Odile, France.
  • Invited
• [Book] XV.小脳の障害と運動失調．1．小脳の解剖と機能．In: 橋本信夫監修、三國信啓、深谷 親編集，「脳神経外科プラックティス. 3.脳神経外科医のための脳機能と局在診断」文光堂. 278-282，2014． 87. (2014)
  • Author(s): 石川欽也．
  • Publisher: 文光堂
• [Book] XV.小脳の障害と運動失調．2．小脳機能障害の分類．In: 橋本信夫監修、三國信啓、深谷 親編集，「脳神経外科プラックティス. 3.脳神経外科医のための脳機能と局在診断」 (2014)
  • Author(s): 石川欽也．
  • Publisher: 文光堂
• [Book] XV.小脳の障害と運動失調．3．小脳機能障害の評価．In: 橋本信夫監修、三國信啓、深谷 親編集，「脳神経外科プラックティス. 3.脳神経外科医のための脳機能と局在診断」 (2014)
  • Author(s): 石川欽也．
  • Publisher: 文光堂
• [Book] 「神経・精神疾患診療マニュアル」 (2013)
  • Author(s): 石川欽也，水澤英洋．
  • Publisher: 日本医師会雑誌.
• [Book] 「小脳と運動失調． 小脳はなにをしているのか」アクチュアル 脳・神経疾患の臨床． (2013)
  • Author(s): 石川欽也，水澤英洋．
  • Publisher: 中山書店
• [Book] 脊髄小脳変性症の治療．薬物治療を中心に．In: 辻 省次 総編集、西澤正豊 専門編集,「小脳と運動失調． 小脳はなにをしているのか」アクチュアル 脳・神経疾患の臨床． (2013)
  • Author(s): 石川欽也，水澤英洋.
  • Publisher: 中山書店
• [Patent(Industrial Property Rights)] ALSの原因タンパク毒性を軽減する核酸 (2014)
  • Inventor(s): 石川欽也、水澤英洋、永井義隆、横田隆徳、石黒太郎、他2名
  • Industrial Property Rights Holder: 石川欽也、水澤英洋、永井義隆、横田隆徳、石黒太郎、他2名
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-12-02
• [Patent(Industrial Property Rights)] 脊髄小脳失調症３１型（SCA31）治療剤 (2014)
  • Inventor(s): 石川欽也、水澤英洋、永井義隆、石黒太郎、佐藤 望、和田圭司
  • Industrial Property Rights Holder: 石川欽也、水澤英洋、永井義隆、石黒太郎、佐藤 望、和田圭司
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-12-02