Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture
Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture
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DOI：
10.1093/hmg/ddn066
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发表时间：
2008-06-15
影响因子：
3.5
通讯作者：
Reiser, Georg
中科院分区：
文献类型：
--
作者：
Hein, Sabine;Schoenfeld, Peter;Reiser, Georg
饱和甚长链脂肪酸（VLCFAs; >= C22:0）在x -连锁肾上腺脑白质营养不良症（X-ALD, OMIM 300100）中积累，这是一种严重的遗传性神经退行性疾病，由过氧化物酶体损伤引起。先前的研究分析了人类和基因敲除动物模型中X-ALD的发展。然而，VLCFA的毒性作用导致进行性和多灶性脱髓鞘、肾上腺功能不全和炎症等严重症状仍不清楚。为了了解VLCFA在大脑中的毒性作用，我们将神经细胞暴露于VLCFA并分析了细胞后果。我们发现少突胶质细胞和星形胶质细胞受到十二烷酸（C22:0）、四烷酸（C24:0）和六烷酸（C24:0）的攻击后在24小时内死亡。VLCFA诱导的线粒体原位去极化和三种脑细胞细胞内Ca2+水平升高为VLCFA的毒性机制提供了指示。有趣的是，VLCFAs对产生髓磷脂的少突胶质细胞的影响最大。在离体线粒体中，VLCFAs通过影响线粒体内膜和促进通透性转变而产生有害影响。总之，我们认为VLCFA具有强大的毒性活性，这是由于线粒体功能障碍和Ca2+失调对细胞产生了巨大的生理影响。这为线粒体为基础的细胞死亡机制在神经退行性疾病与过氧化物酶体缺陷和随后的VLCFA积累提供了第一个证据。
Saturated very long chain fatty acids (VLCFAs; >= C22:0) accumulate in X-linked adrenoleukodystrophy (X-ALD, OMIM 300100), a severe hereditary neurodegenerative disease, due to peroxisomal impairment. Previous studies analysed the development of X-ALD in humans and gene knockout animal models. However, the toxic effect of VLCFA leading to severe symptoms with progressive and multifocal demyelination, adrenal insufficiency and inflammation still remains unclear. To understand the toxic effects of VLCFA in the brain, here we exposed neural cells to VLCFA and analysed the cellular consequences. We found that oligodendrocytes and astrocytes challenged with docosanoic- (C22:0), tetracosanoic- (C24:0) and hexacosanoic acids (C24:0) die within 24 h. VLCFA-induced depolarization of mitochondria in situ and increased intracellular Ca2+ level in all three brain cell types provides indications about the mechanism of toxicity of VLCFA. Interestingly, VLCFAs affect to the largest degree the myelin-producing oligodendrocytes. In isolated mitochondria, VLCFAs exert a detrimental effect by affecting the inner mitochondrial membrane and promoting the permeability transition. In conclusion, we suggest that there is a potent toxic activity of VLCFA due to dramatic cell physiological effects with mitochondrial dysfunction and Ca2+ deregulation. This provides the first evidence for mitochondrial-based cell death mechanisms in neurodegenerative disease with peroxisomal defects and subsequent VLCFA accumulation.