The Journal of Membrane Biology ( IF 2.3 ) Pub Date : 2021-01-11 , DOI: 10.1007/s00232-020-00159-6 Daniel E Otzen 1 , Dina Morshedi 2 , Hossein Mohammad-Beigi 1 , Farhang Aliakbari 2
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Abstract
Thanks in large part to the seminal work of Steve White and his colleagues, we appreciate the “ordered complexity” of the lipid bilayer and how it impacts the incorporation of integral membrane proteins as well as more peripherally associated proteins. Steve’s work also provides a vital foundation to tackle another challenge: cytotoxic oligomeric complexes which accumulate in various neurodegenerative diseases. These oligomers have a relatively fluid structure and interact with many different proteins in the cell, but their main target is thought to be the phospholipid membrane, either the plasma membrane or internal organelles such as the mitochondria. This fascinating encounter between two essentially fluid phases generates a more disordered membrane, and presumably promotes uncontrolled transport of small metal ions across the membrane barrier. Happily, this unwanted interaction may be suppressed by mobilizing the phospholipid bilayer into its own defense. Extruded nanolipoparticles (NLPs) consisting of DPPC lipids, cholesterol and PEG2000 are excellent vehicles to take up small “oligomer-bashing” hydrophobic molecules such as baicalein and transport them with increased half-life in the plasma and with markedly more efficient crossing of the blood–brain barrier. Thus the bilayer has a triple role in this account: a safe space for a reactive hydrophobic small molecule, a barrier to cross to deliver a drug payload and a target to protect against oligomer attacks. NLPs containing small hydrophobic molecules show great promise in combating neurodegenerative diseases in animal models and may serve as an example of the White approach: applying robust physical–chemical principles to deal with biological problems involving phospholipid membranes.
Graphic Abstract
中文翻译：
双层的三重作用：使用纳米脂质体交叉和保护细胞膜
摘要
在很大程度上感谢史蒂夫怀特和他的同事的开创性工作，我们欣赏脂质双层的“有序复杂性”以及它如何影响整合膜蛋白以及更多外围相关蛋白的掺入。Steve 的工作还为应对另一个挑战提供了重要的基础：在各种神经退行性疾病中积累的细胞毒性寡聚体复合物。这些寡聚体具有相对流动的结构并与细胞中的许多不同蛋白质相互作用，但它们的主要目标被认为是磷脂膜，无论是质膜还是线粒体等内部细胞器。两个基本流体相之间的这种迷人的相遇产生了一个更加无序的膜，并且可能促进了小金属离子不受控制地跨膜屏障的传输。令人高兴的是，可以通过将磷脂双层调动到自身的防御中来抑制这种不需要的相互作用。由 DPPC 脂质、胆固醇和 PEG2000 组成的挤压纳米脂质颗粒 (NLP) 是吸收小的“低聚体”疏水分子（如黄芩素）并以增加的血浆半衰期和显着更有效地穿过血液的方式运输它们的优秀载体——脑屏障。因此，双层在这个帐户中具有三重作用：反应性疏水小分子的安全空间、传递药物有效载荷的屏障和防止寡聚体攻击的目标。含有疏水性小分子的 NLP 在动物模型中显示出对抗神经退行性疾病的巨大希望，并且可以作为 White 方法的一个例子：
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