Plasmalogens participate in very-long-chain fatty acid-induced pathology
Plasmalogens participate in very-long-chain fatty acid-induced pathology
复制标题
DOI：
10.1093/brain/awn295
复制
发表时间：
2009-02-01
期刊：
影响因子：
14.5
通讯作者：
Wanders, Ronald J. A.
中科院分区：
文献类型：
--
作者：
Brites, Pedro;Mooyer, Petra A. W.;Wanders, Ronald J. A.
过氧化物酶体是负责多种代谢途径的细胞器，包括缩醛磷脂（一类磷脂）的生物合成和极长链脂肪酸（VLCFA）的氧化。缺乏过氧化物酶体或其任何正常功能的功能障碍是人类过氧化物酶体障碍的细胞基础。在这里，我们使用小鼠模型来理解和定义介导过氧化物酶体功能障碍引起的病理生理后果的生化和细胞决定因素。我们使用Pex7和Abcd 1敲除（KO）小鼠研究了细胞缩醛磷脂和VLCFA在肝脏、睾丸和神经组织中蓄积的作用和影响。此外，我们还产生了Pex7：Abcd 1双KO小鼠，以研究不同的过氧化物酶体功能障碍如何调节细胞功能和病理学。我们发现，缩醛磷脂作为基本结构磷脂发挥作用，并保护细胞免受VLCFA积累引起的损伤。在睾丸中，缩醛磷脂保护精母细胞免受VLCFA诱导的变性和凋亡。在神经组织中，我们发现胶质增生，炎性脱髓鞘和轴突病变引起的积累VLCFA调制的缩醛磷脂。我们的研究结果表明，正常的过氧化物酶体功能的重要性，并允许了解过氧化物酶体功能障碍的病理因果关系。缺乏缩醛磷脂的神经组织更容易受损，这说明缩醛磷脂在包括齐薇格综合征和X连锁肾上腺脑白质营养不良在内的过氧化物酶体疾病中的重要性。
Peroxisomes are organelles responsible for multiple metabolic pathways including, the biosynthesis of plasmalogens, a class of phospholipids, and the -oxidation of very-long-chain fatty acids (VLCFA). Lack of peroxisomes or dysfunction in any of their normal functions is the cellular basis for human peroxisomal disorders. Here we used mouse models to understand and define the biochemical and cellular determinants that mediate the pathophysiological consequences caused by peroxisomal dysfunctions. We investigated the role and effects of cellular plasmalogens and VLCFA accumulation in liver, testis and nervous tissue using Pex7 and Abcd1 knockout (KO) mice. In addition, we also generated a Pex7:Abcd1 double KO mouse to investigate how different peroxisomal dysfunctions modulate cellular function and pathology. We found that plasmalogens function as fundamental structural phospholipids and protect cells from damage caused by VLCFA accumulation. In testis, plasmalogens protect spermatocytes from VLCFA-induced degeneration and apoptosis. In nervous tissue, we found that gliosis, inflammatory demyelination and axonopathy caused by accumulation of VLCFA are modulated by plasmalogens. Our findings demonstrate the importance of normal peroxisomal functioning and allow the understanding of the pathological causality of peroxisomal dysfunctions. Nervous tissue deficient in plasmalogens is more prone to damage, illustrating the importance of plasmalogens in peroxisomal disorders including Zellweger syndrome and X-linked adrenoleukodystrophy.