Relationship between neuronal death and inclusion body formation

• Project/Area Number: 19591026
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Department of Clinical Research, National Hospital Organization Utano National Hospital
• Principal Investigator: SAWADA Hideyuki Department of Clinical Research, National Hospital Organization Utano National Hospital, 宇多野病院臨床研究部, 臨床研究部長 (30335260)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Kenji 独立行政法人国立病院機構, 宇多野病院臨床研究部, 研究員 (50378775)
• Co-Investigator(Renkei-kenkyūsha): IZUMI Yasuhiko 京都大学, 大学院・薬学研究科, 助教 (60456837)
• 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: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 神経細胞死 / パーキンソン病 / オリゴマー / ドパミン / ミトコンドリア / ゲルろ過 / 加齢 / 不溶タンパク / 多系統萎縮症 / プロテアソーム / Lewy小体 / αシヌクレイ

Research Abstract

パーキンソン病は、ドパミン神経の選択的細胞死とLewy小体と呼ばれる神経細胞台風入隊の出現を特徴とする神経変性疾患である。Lewy小体の主要な構成要素にはαシヌクレインが含まれており、αシヌクレインの3重複が家族性パーキンソン病を引き起こすことから両者は偶然の合併でなく、この関係を理解することは、パーキンソン病の病態の理解に重要な治験をもたらす。パーキンソン病では、脳内ドパミン神経のみならずノルアドレナリン神経、セロトニン神経、さらに末梢神経である交感神経節後神経線維にも変性と封入体形成を生じる。これらの点からは、カテコラミンを神経細胞内に含有することが、神経細胞重要な要素であり、本研究では、この点に重点を置いて検討を進めた。その結果、神経細胞内のドパミンが神経細胞死に関与しており、ドパミントランスポーターの抑制により神経細胞死が回避できること(Izumiet al., 2008)、ドパミン負荷により、2量体から10量体のαシヌクレインが実際に細胞内に増大するものの、より分子量の大きなフィブリルは形成されず、封入体は形成されないこと(Yamakawa et al., 2009)が示された。これらの結果からは、ドパミン負荷はαシヌクレインのオリゴマー形成と細胞死に関与するが、封入体形成には直接関与していない可能性が考えられる。

Research Products

• [Journal Article] Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson's disease model (2009)
  • Author(s): Takeuchi H, Yangagida T, Inden M, Takata K, Kitamura Y, Yamakawa K, Sawada H, Izumi Y, Yamamoto N, Kihara T, Uemura K, Inoue H, Taniguchi T, Akaike A, Takahashi R, Shimahama S.
  • Journal Title: J Nerosci Res 87 Pages: 576-585
• [Journal Article] Vulnerability to glutamate toxicity of dopaminergic neurons is dependent on endogenous dopamine and MAPK activation (2009)
  • Author(s): Izumi Y, Yamamoto N, Matsuo T, Wakita S. Takeuchi H, Kume T, Katsuki H, Sawada H, Akaike A.
  • Journal Title: J Neurochem 110 Pages: 745-755
• [Journal Article] Diagnostic accuracy of cardiac metaiodobenzylguanidine scintigraphy in Parkinson disease (2009)
  • Author(s): Sawada H, Oeda T, Yamamoto K, Kitagawa N, Mizuta E, Hosokawa R, Ohba M, Nishio R, Yamakawa K, Takeuchi H, Shimohama S, Takahashi R, Kawamura T.
  • Journal Title: Eur J Neurol 16 Pages: 174-182
• [Journal Article] Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson's disease models (2009)
  • Author(s): Takeuchi H, Yanagida T, Inden M, Takata K, Kitamura Y, Yamakawa K, Sawada H, Izumi Y, Yamamoto N, Kihara T, Uemura K, Inoue H, Taniguchi T, Akaike A, Takahashi R, Shimohama S.
  • Journal Title: J. Neurosci. Res 87 Pages: 576-585
  • Peer Reviewed
• [Journal Article] High risk factors for valvular heart disease from dopamine agonists in patients with Parkinson's disease (2009)
  • Author(s): Oeda T, Masaki M, Yamamoto K, Mizuta E, Kitagawa N, Isono T, Taniguchi S, Doi K, Yaku H, Yutani C, Kawamura T, Kuno S, Sawada H.
  • Journal Title: J. Neural Transm 116 Pages: 171-178
  • Peer Reviewed
• [Journal Article] Diagnositc accuracy of cardiac metaiodobenzylguanidine scintigraphy in Parkinson disease (2009)
  • Author(s): Sawada H, Oeda T, Yamamoto K, Kitagwa N, Mizuta E, Hosokawa R, Ohba M, Nishio R, Yamakawa K, Takeuchi H, Shimohama S, Takahashi R, Kawamura T.
  • Journal Title: Eur. J. Neurol 16 Pages: 174-182
  • Peer Reviewed
• [Journal Article] Vulnerability to glutamate toxicity of dopaminergic Neurons is dependent on endogenous dopamine and MAPK activation (2009)
  • Author(s): Izumi Y, Yamamoto N, Matsuo T, Wakita S, Takeuchi H, Kume T, Katsuki H, Sawada H, Akaike A.
  • Journal Title: J. Neurochem (in press)
  • Peer Reviewed
• [Journal Article] Regulation of intracellular dopamine levels by dopaminergic drugs : Involvement of vesicular monoamine transporter (2008)
  • Author(s): Izumi Y, Yamamoto N, Kume T, Katsuki H, Sawada H, Akaike A.
  • Journal Title: Eur J Pharmacol 582 Pages: 52-61
• [Journal Article] Regulation of intracellular dopamine levels by dopaminergic drugs : involvement of vesicular transporter. (2008)
  • Author(s): Izumi Y, et. al.
  • Journal Title: Eur. J. Pharmacol. 582 Pages: 52-61
  • Peer Reviewed
• [Journal Article] パーキンソン病における交感神経節後線維の障害 (2007)
  • Author(s): 澤田秀幸
  • Journal Title: 自律神経 44巻 Pages: 180-186
  • NAID: 10019842283
• [Journal Article] パーキソン病における交感神経節後線維の障害 (2007)
  • Author(s): 澤田秀幸
  • Journal Title: 自律神経 44 Pages: 180-186
  • Peer Reviewed
• [Journal Article] Dopamine facilitates a-synuclein oligomerization in human neuroblastoma SH-SY5Y cells
  • Author(s): Yamakawa K, Izumi Y, Takeuchi H, Yamamoto N, Kume T, Akaike A, Takahashi R, Shimohama S, Sawada H.
  • Journal Title: Biochem Biophys Res Comm (in press)
• [Presentation] ドパミン受容体リガンドによるドパミン含有量低下作用機序の解明 (2008)
  • Author(s): 泉安彦, 山本憲幸, 久米利明, 澤田秀幸, 赤池昭紀
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜市
  • Year and Date: 2008-05-16
• [Presentation] ニコチンの中脳ドーパミン(DA)神経保護と凝集体形成への効果 (2008)
  • Author(s): 竹内啓喜, 植村健吾, 井上治久, 高橋良輔, 北村佳久, 谷口隆之, 赤池昭紀, 澤田秀幸, 下濱俊
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜市
  • Year and Date: 2008-05-15
• [Presentation] Nicotine provides protective effects in dopaminergic neurons via the nicotinic receptors. (2007)
  • Author(s): Takeuchi H, Yanagida K, Takata K, et. al.
  • Organizer: XVIIth WFN World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Amsterdam, Netherland
  • Year and Date: 2007-12-13
• [Presentation] Cardiac metaiodobenzylguanidine scintigraphy as a peripheral biomarker for the diagnosis of Parkinson disease. (2007)
  • Author(s): Sawada H, Oeda T, Yamamoto K, et. al.
  • Organizer: XVIIth WFN World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Amsterdam, Netherland
  • Year and Date: 2007-12-13
• [Presentation] Induction of heme oxygenase-1 by proteasome inhibition is involved in the protection of dopaminergic neurons : implication of ubiquitin-proteasome degradation. (2007)
  • Author(s): Yamamoto N, Sawada H, Izumi Y, et. al.
  • Organizer: XVIIth WFN World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Amsterdam, Netherland
  • Year and Date: 2007-12-12
• [Presentation] Induction of heme oxygenase-1 by proteasome inhibition is involved in the protection of dopaminergic neurons : implication of ubiquitin-proteasome degradation (2007)
  • Author(s): Yamamoto N, Sawada H, Izumi Y, et al.
  • Organizer: XVIIth WFN World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Amsterdam, Netherland
• [Presentation] Nicotine provides protective effects in dopaminergic neurons via the nicotinic receptors (2007)
  • Author(s): Takeuchi H, Yanagida K, Takata K, et al.
  • Organizer: XVIIth WFN World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Amsterdam, Netherland
• [Presentation] Cardiac metaiodobenzylguanidine scintigraphy as a peripheral biomarker for the diagnosis of Parkinson disease (2007)
  • Author(s): Sawada H, Oeda T, Yamamoto K, et al.
  • Organizer: XVIIth WFN World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Amsterdam, Netherland
• [Patent(Industrial Property Rights)] パーキンソン病診断キット (2003)
  • Inventor(s): 澤田秀幸, 下濱俊
  • Industrial Property Number: 2003-405942
  • Filing Date: 2003-12-04