Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases.
Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases.
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DOI：
10.1017/s1462399410001602
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发表时间：
2010-09-01
影响因子：
6.2
通讯作者：
Yahi N
中科院分区：
文献类型：
--
作者：
Fantini J;Yahi N
阿尔茨海默病、帕金森病等神经退行性疾病涉及一系列的脑 蛋白质，称为“淀粉样蛋白”，具有特殊的 构象可塑性和自聚集的高倾向。虽然 淀粉样蛋白杀死神经细胞的机制还不完全清楚， 一个共同的特征是非结构化淀粉样单体的浓度 二维膜晶格膜结合的单体经历一系列的 脂质依赖性构象变化，导致形成不同的低聚物， 毒性富含β折叠结构（环形孔，淀粉样纤维）或 α-螺旋结构（跨膜通道）。浓缩膜纳米或 由鞘脂和胆固醇形成的微区是结合的特权位点 和淀粉样蛋白的寡聚化。通过控制 非结构化单体和α或β构象异构体（分子伴侣效应）， 鞘脂可以抑制或刺激淀粉样蛋白的寡聚化， proteins.胆固醇具有双重作用：调节蛋白质-鞘脂 通过微调鞘脂构象（间接效应）的相互作用，以及 通过直接结合淀粉样蛋白生成促进孔（或通道）形成 proteins.在分子相互作用的背景下， 与年龄和疾病相关的脑脂质表达的演变将有助于理解 淀粉样蛋白是如何诱导神经毒性并刺激 神经退行性疾病的创新疗法。
Alzheimer, Parkinson and other neurodegenerative diseases involve a series of brain proteins, referred to as ‘amyloidogenic proteins’, with exceptional conformational plasticity and a high propensity for self-aggregation. Although the mechanisms by which amyloidogenic proteins kill neural cells are not fully understood, a common feature is the concentration of unstructured amyloidogenic monomers on bidimensional membrane lattices. Membrane-bound monomers undergo a series of lipid-dependent conformational changes, leading to the formation of oligomers of varying toxicity rich in β-sheet structures (annular pores, amyloid fibrils) or in α-helix structures (transmembrane channels). Condensed membrane nano- or microdomains formed by sphingolipids and cholesterol are privileged sites for the binding and oligomerisation of amyloidogenic proteins. By controlling the balance between unstructured monomers and α or β conformers (the chaperone effect), sphingolipids can either inhibit or stimulate the oligomerisation of amyloidogenic proteins. Cholesterol has a dual role: regulation of protein–sphingolipid interactions through a fine tuning of sphingolipid conformation (indirect effect), and facilitation of pore (or channel) formation through direct binding to amyloidogenic proteins. Deciphering this complex network of molecular interactions in the context of age- and disease-related evolution of brain lipid expression will help understanding of how amyloidogenic proteins induce neural toxicity and will stimulate the development of innovative therapies for neurodegenerative diseases.