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Formation of ion chyannels by amyloidogenic proteins and screening for protective substances

淀粉样蛋白形成离子通道及保护物质的筛选

基本信息

批准号：
14572106
负责人：
KAWAHARA Masahiro
金额：
$ 2.56万
依托单位：
School of Pharmaceutical Sciences, Kyushu University of Health and Welfare (2003-2005)Tokyo Metropolitan Organization for Medical Research (2002)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

The conformational changes of Alzheimer's β-amyloid protein (AβP) enhance its neurotoxicity, and finally lead to Alzheimer's pathogenesis. Recent studies have suggested that a common mechanism is based on the diverse diseases termed "conformational diseases" including other neurodegenerative diseases such as prion diseases, Parkinson's disease, and Huntington's disease. These diseases share similarity in the formation of β-sheet containing amyloid fibrils by disease-related proteins such including prion protein, a-synuclein, polyglutamine and the introduction of apoptotic degeneration. Although the molecular mechanism of neurodegeneration induced by these conformational disease-related proteins remains elusive, these proteins have the ability to directly incorporate into membranes and to form calcium-permeable ion channels. In this research, we have investigated the detailed characteristics of channel formation by amyloidogenic proteins including beta-amyloid protein, prion protein fragment peptides, alpha-synuclein fragment peptides using Ca imaging system. We found that these proteins cause rapid increase of intracellular Ca levels. Amyloid peptides composed by D-amino acid residues also cause similar Ca increase. No known transmitter inhibitors or channel blockers inhibit the Ca changes. Therefore, we conclude that Ca increase caused by these amyloidogenic peptides are based on the "amyloid channels". Furthermore, we searched substances which prevent Ca increase induced by amyloid proteins for the aim of screening possible treatment for theses neurodegenerative diseases. Several neurosteroids marked inhibit the Ca increase. Moreover, we investigated the effects of trace metals which effect the conformational changes of amyloidogenic proteins.

阿尔茨海默病β-淀粉样蛋白（AβP）的构象变化增强了其神经毒性，最终导致阿尔茨海默病的发病。最近的研究表明，一种共同的机制是基于称为“构象疾病”的多种疾病，包括其他神经退行性疾病，如朊病毒疾病、帕金森病和亨廷顿病。这些疾病在通过疾病相关蛋白（例如包括朊病毒蛋白、α-突触核蛋白、多聚谷氨酰胺）形成含有淀粉样纤维的β-折叠和引入凋亡变性方面具有相似性。虽然这些构象疾病相关蛋白诱导的神经变性的分子机制仍然难以捉摸，但这些蛋白具有直接掺入膜并形成钙渗透性离子通道的能力。在本研究中，我们使用Ca成像系统研究了淀粉样蛋白形成蛋白包括β-淀粉样蛋白、朊病毒蛋白片段肽、α-突触核蛋白片段肽形成通道的详细特征。我们发现，这些蛋白质引起细胞内Ca水平的快速增加。由D-氨基酸残基组成的淀粉样肽也引起类似的Ca增加。没有已知的递质抑制剂或通道阻滞剂抑制Ca变化。因此，我们得出结论，这些淀粉样蛋白生成肽引起的钙增加是基于“淀粉样蛋白通道”。此外，我们寻找阻止淀粉样蛋白诱导的Ca增加的物质，以筛选这些神经退行性疾病的可能治疗方法。几种神经甾体显著抑制Ca的增加。此外，我们还研究了微量金属对淀粉样蛋白构象变化的影响。