Khan Mushfiquddin, Singh Jaspreet, Singh Inderjit
Department of Pediatrics, Darby Children Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
J Neurochem. 2008 Aug;106(4):1766-79. doi: 10.1111/j.1471-4159.2008.05513.x. Epub 2008 Jun 7.
In cerebral adrenoleukodystrophy (cALD), an accumulation of very long chain fatty acids stems from a defect of the peroxisomal ALD protein (ALDP) and results in the loss of myelin/oligodendrocytes, induction of inflammatory disease and mental deterioration. In brain white matter of cALD patients, we observed not only increased levels of very long chain fatty acid but also reduced levels of plasmenylethanolamine (PlsEtn) and increased levels of reactive oxygen species (ROS). The loss of PlsEtn was greatest in the plaque area and lesser but significant at histologically normal-looking areas of the cALD brain. The reduction in PlsEtn was related to oxidative stress, as supported by increased levels of reactive lipid aldehydes (4-hydroxynonenal and acrolein) and deleterious oxidized proteins (protein carbonyl) in all areas of the cALD brain. This inverse relationship between the levels of PlsEtn and reactive oxygen species (ROS) was further supported in an in vitro study using gene-silencing for dihydroxyacetone phosphate-acyl transferase, a key enzyme for PlsEtn biosynthesis. Levels of PlsEtn were also found decreased in vitro following gene-silencing for the ALDP/ALD-related protein. Furthermore, low levels of PlsEtn were detected in brain white matter of ALDP knock out (KO) mice. A treatment of ALDP KO mice with lovastatin increased PlsEtn levels in the brain. Further, in an in vitro study, lovastatin treatment of rat C6 glial cells increased PlsEtn biosynthesis and reduced the cytokine-induced ROS accumulation. In summary, this study reports that altered metabolism of PlsEtn and ROS in cALD may be corrected by lovastatin treatment.
在脑型肾上腺脑白质营养不良（cALD）中，超长链脂肪酸的积累源于过氧化物酶体ALD蛋白（ALDP）的缺陷，导致髓鞘/少突胶质细胞丢失、炎症性疾病的诱导和智力衰退。在cALD患者的脑白质中，我们不仅观察到超长链脂肪酸水平升高，还观察到缩醛磷脂酰乙醇胺（PlsEtn）水平降低以及活性氧（ROS）水平升高。PlsEtn的丢失在斑块区域最为严重，而在cALD脑的组织学外观正常区域则较轻但仍很显著。cALD脑中所有区域的反应性脂质醛（4-羟基壬烯醛和丙烯醛）和有害氧化蛋白（蛋白质羰基）水平升高，支持了PlsEtn的减少与氧化应激有关。在一项使用基因沉默磷酸二羟丙酮-酰基转移酶（PlsEtn生物合成的关键酶）的体外研究中，进一步支持了PlsEtn水平与活性氧（ROS）之间的这种反比关系。在对ALDP/ALD相关蛋白进行基因沉默后，体外也发现PlsEtn水平降低。此外，在ALDP基因敲除（KO）小鼠的脑白质中检测到低水平的PlsEtn。用洛伐他汀治疗ALDP KO小鼠可提高脑中PlsEtn水平。此外，在一项体外研究中，用洛伐他汀治疗大鼠C6胶质细胞可增加PlsEtn生物合成并减少细胞因子诱导的ROS积累。总之，本研究报告cALD中PlsEtn和ROS代谢的改变可能通过洛伐他汀治疗得到纠正。
