Castegna Alessandra, Lauderback Christopher M, Mohmmad-Abdul Hafiz, Butterfield D Allan
Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
Brain Res. 2004 Apr 9;1004(1-2):193-7. doi: 10.1016/j.brainres.2004.01.036.
Membrane lipid bilayer asymmetry is maintained by the ATP-dependent enzyme flippase. An early signal of synaptosomal apoptosis is the loss of phospholipid asymmetry and the appearance of phosphatidylserine (PS) in the outer leaflet of the membrane. Two highly reactive products of lipid peroxidation, 4-hydroxynonenal (HNE) and acrolein, both elevated in Alzheimer's disease (AD) brain, have been shown to induce apoptosis and disrupt cellular ion homeostasis. These reactive aldehydes can structurally modify proteins by covalent interaction and inhibit enzyme function. Phospholipid asymmetry of PS is maintained by the ATP-requiring enzyme flippase. We have investigated the inactivation of the transmembrane enzyme aminophospholipid-translocase (or flippase) by HNE and acrolein. Flippase activity depends on a critical cysteine residue, a possible site of covalent modification by HNE or acrolein. The present study demonstrates that these alkenals induce the appearance of PS on the outer bilayer lamellae and suggests that increases in intracellular Ca(2+) might not be the sole cause for loss of flippase activity. Rather, other mechanisms that could modulate the function of flippase might be important in phospholipid asymmetry disruption. These results are discussed with potential relevance to neuronal loss in Alzheimer's disease brain.
膜脂双层不对称性由ATP依赖的翻转酶维持。突触体凋亡的早期信号是磷脂不对称性丧失以及膜外小叶中磷脂酰丝氨酸（PS）的出现。脂质过氧化的两种高反应性产物，4-羟基壬烯醛（HNE）和丙烯醛，在阿尔茨海默病（AD）脑内均升高，已被证明可诱导凋亡并破坏细胞离子稳态。这些反应性醛可通过共价相互作用对蛋白质进行结构修饰并抑制酶功能。PS的磷脂不对称性由需要ATP的翻转酶维持。我们研究了HNE和丙烯醛对跨膜酶氨基磷脂转位酶（或翻转酶）的失活作用。翻转酶活性取决于一个关键的半胱氨酸残基，这可能是HNE或丙烯醛进行共价修饰的位点。本研究表明，这些烯醛可诱导外双层薄片上出现PS，并提示细胞内Ca(2+)升高可能不是翻转酶活性丧失的唯一原因。相反，其他可能调节翻转酶功能的机制在磷脂不对称性破坏中可能很重要。讨论了这些结果与阿尔茨海默病脑内神经元丢失的潜在相关性。
