Development of DNA microarray-based reseqeuncing system for neurological diseases.

• Project/Area Number: 16209028
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: TSUJI Shoji The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (70150612)
• Co-Investigator(Kenkyū-buntansha): GOTO Jun The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (10211252) ; TAKAHASHI Yuji The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (00372392)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥49,660,000 (Direct Cost: ¥38,200,000、Indirect Cost: ¥11,460,000); Fiscal Year 2005: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2004: ¥31,070,000 (Direct Cost: ¥23,900,000、Indirect Cost: ¥7,170,000)
• Keywords: Parkinson disease / neurodegenerative diseases / DNA microarray / DNA chip / resequencing / disease-associated genes / PCR / molecular genetics / DNA microarray / DNA chip / 疾患関連遺伝子 / 分子遺伝学 / DNA micro array

Research Abstract

The purpose of this project is to develop a high throughput mutational analysis system for neurological diseases. The approach consists of 1.to develop microarray bases reseqeuncing of causative genes for neurological diseases. 2.application of comprehensive analysis of candidate genes for sporadic diseases. and 3.analysis of phenotypic variations bases on comprehensive mutational analysis. To accomplish, these aims, we have developed DNA microarrays for Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, adrenoleukodsytrophy, familial spastic paraplegia. We have confirmed that the sensitivity and specificity of DNA microarray-bases reseqeuncing are comparable to those based on dideoxynucleotide chain terminator method. We have applied DMA microarray-based reseqeuncing for comprehensive mutational analysis of causative genes for 43 patients with spastic paraplegia. We have identified 7 patients with SPG4 and a patient with SPG3A. Among the SPG4 patients, there are two sporadic cases, suggesting reduced penetrance of the mutations. Thus, we have demonstrated that the high throughput DNA microarray-based resegeuncing system is highly useful for molecular dissection of neurological diseases including Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, adrenoleukodsytrophy, familial spastic paraplegia

Research Products

• [Journal Article] Polyglutamine represses cAMP-mediated transcription without aggregate formation. (2005)
  • Author(s): Takahashi T, Nozaki K, Tsuji S, Nishizawa M, Onodera O.
  • Journal Title: Neuroreport 16(3)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interference with activity-dependent transcriptional activation of BDNF gene depending upon the expanded polyglutamines in neurons. (2005)
  • Author(s): Miyashita T, Tabuchi A, Fukuchi M, Hara D, Kisukeda T, Shimohata T, Tsuji S, Tsuda M
  • Journal Title: Biochem Biophys Res Commun 333(4)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Spinocerebellar ataxia type 15. (2005)
  • Author(s): Gardner RJ, Knight MA, Hara K, Tsuji S, Forrest SM, Storey E.
  • Journal Title: Cerebellum 4(1) Pages: 47-50
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. (2005)
  • Author(s): Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H, Tsuji S, Obata F.
  • Journal Title: Ann Neurol 57(6)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches - Augmentation of transcriptional Activation as a potential therapeutic strategy for polyglutamine disease/ (2005)
  • Author(s): Shimohata M, Shimohata T, Igarashi S, Naruse S, Tsuji S
  • Journal Title: J. Neurochem 93 Pages: 654-663
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] O.Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation. (2005)
  • Author(s): Takahashi T, Nozaki K, Tsuji S, Nishizawa M, Onodera
  • Journal Title: Neuroreport 16(3) Pages: 295-299
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interference with activity-dependent transcriptional activation of BDNF gene depending upon the expanded polyglutamines in neurons. (2005)
  • Author(s): Miyashita T, Tabuchi A, Fukuchi M, Hara D, Kisukeda T, Shimohata T, Tsuji S, Tsuda M.
  • Journal Title: Biochem Biophys Res Commun 333(4) Pages: 1241-1248
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Spinocerebellar ataxia type 15. (2005)
  • Author(s): Gardner RJ, Knight MA, Hara K, Tsuji S, Forrest SM, Storey E.
  • Journal Title: Cerebellum 5;4(1) Pages: 47-50
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches-Augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases/ (2005)
  • Author(s): Shimohata, M, Shimohata, T, Igarashi, S, Naruse, S, Tsujil, S
  • Journal Title: J.Neurochem 93 Pages: 654-663
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation. (2005)
  • Author(s): Takahashi T, Nozaki K, Tsuji S, Nishizawa M, Onodera O.
  • Journal Title: Neuroreport 16(3) Pages: 295-299
• [Journal Article] Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches - Augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases (2005)
  • Author(s): Shimohata, M, Shimohata, T, Igarashi, S, Naruse, S, Tsuji, S.
  • Journal Title: J.Neurochem 93 Pages: 654-663
• [Journal Article] Adult-onset leukocncephalopathy with vanishing whitte matter with a missense mutation in EIF2B5. (2004)
  • Author(s): Ohtake H, Shimohata, T, Terajima, K, Kimura, T, Jo, R, Kaseda, R, Iizuka, O, Takano, M, Akaiwa, Y, Goto, H, Kobayashi, H, Sugai, T, Muratake, T, Hosoki, T, Shioiri, T, Okamoto, K, Onodera, O, Tanaka, K, Someya, T, Nakada, T, Tsuji, S
  • Journal Title: Neurology 62 Pages: 1601-3
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5 (2004)
  • Author(s): Ohtake H, Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri, T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S.
  • Journal Title: Neurology 62 Pages: 1601-1603
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Five year follow up of a patient with spinal and bulbar muscular atrophy treated with leuprorelin. (2004)
  • Author(s): Shimohata T, Kimura T, Nishizawa M, Onodera O, Tsuji S.
  • Journal Title: J Neurol Neurosurg Psychiatry 75 Pages: 1206-1207
• [Journal Article] Aprataxin, the causative protein for early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is a nuclear protein with a potential role as a nucleotide repair protein. (2004)
  • Author(s): Sano, Y., Date, H, Igarashi, S, Onodera, O, Oyake, M, Takahashi, T, Hayashi, S, Morimatsu, M, Takahashi, H, Makifuchi, T, Fukuhara, N, Tsuji, S.
  • Journal Title: Ann.Neurol. 55 Pages: 241-249
• [Journal Article] Japanese SCA families with a distinct phenotype linked to a locus overlapping with SCA15 locus (2004)
  • Author(s): Hara, K, Fukushima, T, Suzuki, T, Shimohata, T, Oyake, M, Ishiguro, H, Hirota, K, Miyashita, A, Kuwano, R, Kurisaki, H, Yomono, H, Goto, J, Kanazawa, I, Tsuji, S
  • Journal Title: Neurol. 62 Pages: 648-651
• [Journal Article] Greenstein, P.Huntington's Disease-like 2 (HDL2) in North America and Japan. (2004)
  • Author(s): Margolis RL, Holmes, S E., Rosenblatt, A., Gourley, L., O'Hearn, E., Ross, C A., Seltzer, W K., Walker, RH., Ashizawa, T., Rasmussen, A., Hayden, M., Almqvist, E W., Harris, J., Fahn, S., MacDonald, M E., Mysore, J., Shimohata, T., Tsuji, S., Potter, N., Nakaso, K., Adachi, Y., Nakashima, K., Bird, T., Krause, A.
  • Journal Title: Ann Neurol 56 Pages: 670-674
• [Journal Article] Beta-synuclein gene alterations in dementia with Lewy bodies. (2004)
  • Author(s): Ohtake H, Limprasert, P., Fan, Y., Onodera, O., Kakita, A., Takahashi, H., Bonner, L T., Tsuang, D W., Murray, I V., Lee, V M., Trojanowski, JQ., Ishikawa, A., Idezuka, J., Murata, M., Toda, T., Bird, T D., Leverenz, J B., Tsuii, S.
  • Journal Title: Neurology 63 Pages: 805-811
• [Journal Article] Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF 2B5. (2004)
  • Author(s): Ohtake H, Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S.
  • Journal Title: Neurology 62 Pages: 1601-1603