Functional analyses of the responsible proteins for familial Parkinson's disease in association with lipid rafts

• Project/Area Number: 18590956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Juntendo University
• Principal Investigator: KUBO Shin-ichiro Juntendo University, School of Medicine, Assistant professor (20327795)
• Co-Investigator(Kenkyū-buntansha): HATTORI Nobutaka Juntendo University, School of Medicine, professor (80218510)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Famililal Parkinson's disease / lipid rafts / LRRK2 / PINK1 / Parkin / DJ-1 / Lipid rafts / 細胞内局在 / ゴルジ体 / シナプス小胞 / パーキンソン病

Research Abstract

This project was designed for elucidating the pathomechanism of Parkinson's disease (PD) through studying familial PD, which occurs via a single gene defect. Among the responsible gene products for familial PD, alpha-synuclein and parkin have been reported to associates with microdomains on the cellular membranes "lipid rafts", which are thought to play important roles in cellular functions such as signal transduction, cytoskeletal organization, and membrane trafficking. In this project, we have elucidated that leucine-rich repeat kinase 2 protein, one of the responsible gene products for autosomal dominant familial PD, associates with lipid rafts. Base on these results, we assumed that interactions between the responsible gene products for familial PD and lipid rafts should be a clue to elucidating the pathomechanism of PD. To study this hypothesis, we overexpressed PINK1, one of the responsible gene products for recessive familial PD, in cultured cells, and fractionated the cells for its distribution in the cells. PINK1 was collected in detergent-insoluble fractions corresponding to lipid rafts. Furthermore, immunocytochemical experiments using these cells indicated its localization to cellular organelles. Interestingly, immunoprecipitation and fluorescent resonance 'energy transfer technique revealed interaction of PINK1 with parkin in the cultured cells overexpressed with these proteins. Based on these results, we elucidated that parkin plays a role to stabilize PINK1 in the cells. Indeed, the expression level of PINK1 in parkin-deficient mice was reduced (manuscript submitted). We also found that DJ-1 protein, one of the responsible gene products for recessive familial PD, associates with synaptosomal membranes, suggesting its role in synaptic functions, fundamental properties of neurons. To clarify the role of DJ-1 in neuronal functions, we are going to analyze the proteins using DJ-1 knockout mice.

Research Products

• [Journal Article] Visual impairment in Parkinson's disease treated with amantadine:Case report and review of the literature (2008)
  • Author(s): Kubo S
  • Journal Title: Parkinsonism Relat Disord 14 Pages: 166-169
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Visual impairment in Parkinson's disease treated with amantadine : Case report and review of the literature (2008)
  • Author(s): Kubo, S., Iwatake, A., Ebihara, N., Murakami, A., Hattori, N
  • Journal Title: Parkinsonism Relat Disord 14 Pages: 166-169
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Leucine-rich repeat kinase 2 associates with lipid rafts (2007)
  • Author(s): Hatano T
  • Journal Title: Hum Mol Genet 16 Pages: 678-690
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Leucine-rich repeat kinase 2 associates with lipid rafts (2007)
  • Author(s): Hatano, T., Kubo, S., Imai, S., Maeda, M., Ishikawa, K., Mizuno, Y., Hattori, N
  • Journal Title: Hum Mol Genet 16 Pages: 678-690
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Leucine-rich repeat kinase 2 associates with lipid rafts. (2007)
  • Author(s): Hatano T et al.
  • Journal Title: Hum Mol Genet. (Mar 6; [Epub ahead of print])
• [Journal Article] Molecular mechanisms of nigral neurodegeneration in Park2 and regulation of parkin protein by other proteins (2006)
  • Author(s): Hattori N
  • Journal Title: J Neural Transm 70 Pages: 205-208
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries (2006)
  • Author(s): Tomiyama H
  • Journal Title: Mov Disord 21 Pages: 1102-1108
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Recessive Parkinson's disease (2006)
  • Author(s): Kubo S
  • Journal Title: Mov Disord 21 Pages: 885-893
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Recessive Parkinson's disease (2006)
  • Author(s): Kubo, S., Hattori, N., Mizuno, Y
  • Journal Title: Mov Disord 21 Pages: 885-893
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular mechanisms of nigral neurodegeneration in Park2 and regulation of parkin protein by other proteins (2006)
  • Author(s): Hattori, N., Machida, Y., Sato, S., Noda, K., Iijima-Kitami, M., Kubo, S., Mizuno, Y
  • Journal Title: J Neural Transm 70 Pages: 205-208
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries (2006)
  • Author(s): Tomiyama, H., Li, Y., Funayama, M., Hasegawa, K., Yoshino, H., Kubo, S., Sato, K., Hattori, T., Lu, CS., Inzelberg, R., Djaldetti, R., Melamed, E., Amouri, R., Gouider-Khouja, N., Hentati, F., Hatano, Y., Wang, M., Imamichi, Y., Mizoguchi, K., Miyajima, H., Obata, F., Toda, T., Farrer, MJ., Mizuno, Y., Hattori, N
  • Journal Title: Mov Disord 21 Pages: 1102-1108
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries. (2006)
  • Author(s): Tomiyama H et al.
  • Journal Title: Mov Disord. 21 Pages: 1102-1108
• [Journal Article] Recessive Parkinson's disease. (2006)
  • Author(s): Kubo S et al.
  • Journal Title: Mov Disord. 21 Pages: 885-893
• [Journal Article] Molecular mechanisms of nigral neurodegeneration in Park2 and regulation of parkin protein by other proteins. (2006)
  • Author(s): Hattori N et al.
  • Journal Title: J Neural Transm. 70 Pages: 205-208
• [Presentation] LRRK2 binds to intracellular organelles (2007)
  • Author(s): Hatano T
  • Organizer: American Neurological Association
  • Place of Presentation: Washington,DC
  • Year and Date: 2007-10-07
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] LRRK2 binds to intracellular organelles (2007)
  • Author(s): Hatano, T
  • Organizer: American Neurological Association
  • Place of Presentation: Washington, DC
  • Year and Date: 2007-10-07
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] LRRK2 associates with lipid rafts (2007)
  • Author(s): Kubo S
  • Organizer: The Movement Disorder Society
  • Place of Presentation: Istanbul
  • Year and Date: 2007-06-04
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 最新医学、別冊 新しい診断と治療のABC (2006)
  • Author(s): 久保 紳一郎
  • Publisher: 最新医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 最新医学・別冊新しい診断と治療のABC (2006)
  • Author(s): 久保 紳一郎
  • Publisher: 最新医学社
• [Book] 塩酸アマンタジン、抗コリン薬の効果と安全性に関するエビデンス。 (2006)
  • Author(s): 久保紳一郎
  • Total Pages: 12
  • Publisher: 最新医学社