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.

阿尔茨海默氏症的β-淀粉样蛋白（AβP）的构象变化增强了其神经毒性，并最终导致阿尔茨海默氏症的发病机理。最近的研究表明，一种共同的机制是基于称为“构象疾病”的潜水疾病，包括其他神经退行性疾病，例如病毒疾病，帕金森氏病和亨廷顿氏病。这些疾病在含有疾病相关蛋白的含有淀粉样蛋白原纤维的β-折叠形成中具有相似性，例如蛋白质蛋白，a-核蛋白，多谷氨酰胺和凋亡变性的引入。尽管这些与构型疾病相关蛋白诱导的神经退行性变性的分子机制仍然难以捉摸，但这些蛋白质具有直接掺入机制并形成可钙渗透的离子通道的能力。在这项研究中，我们研究了淀粉样蛋白蛋白的通道形成的详细特征，包括β-淀粉样蛋白，prion蛋白蛋白片段肽，使用Ca成像系统的α-突触核蛋白碎片肽。我们发现这些蛋白质会导致细胞内Ca水平的迅速增加。由D-氨基酸组成的淀粉样蛋白肽也会导致相似的Ca增加。没有已知的发射器抑制剂或通道阻滞剂抑制CA的变化。因此，我们包括由这些淀粉样蛋白生成的宠物引起的CA增加是基于“淀粉样通道”的。此外，我们搜索了防止淀粉样蛋白诱导的CA增加的物质，目的是筛查可能治疗这些神经退行性疾病。几种标志着抑制CA的神经类似物。此外，我们研究了痕量金属的影响，从而影响淀粉样蛋白的构象变化。