MOLECULAR PATHOLOGY AND PATHOGENESIS OF X-ADRENOLEUKODYSTROPHY

这个项目的长期目标是了解分子 X连锁肾上腺脑白质营养不良(ALD)的病理和发病机制 致命的神经退行性疾病。有缺陷的过氧化体激活 超长链脂肪酰辅酶A合成超长链脂肪酸 合成酶(VLCs)导致ALD患者VLCFA水平升高。这个 ALD(Aldp)缺陷基因的产物是一种过氧体 膜蛋白，是三磷酸腺苷结合盒(ABC)的一员 膜转运蛋白家族，在结构上不相似 酰辅酶A合成酶。尽管ALDP显然是正常所需的 VLCFA的降解，它不具有VLCs活性，它的 生化功能及其在ALD中的作用尚未阐明。然而， 这种蛋白的突变会导致毁灭性的临床病理。至 开发临床治疗方法并研究其病理生理学。 疾病，ALDP功能的遗传和生化研究将是 使用。将克隆vlcs基因并对其基因产物进行鉴定 为了阐明VLC之间的关系，以前认为 ALD的缺陷，到ALDP。两种类型的诱变策略，随机 的特定区域的诱变和破坏 蛋白质，将用于分析ALDP的结构和功能。 因为ABC蛋白质通常需要与其他蛋白质相互作用才能 将使用功能、遗传和生化方法来阐明 ALDP与蛋白质的相互作用。最后，ALDP对VLCFA的影响 几种细胞类型的代谢(包括神经源性细胞)和 在模型膜中将被检查。这些研究将导致更好的 了解ALDP的功能以及ALDP和VLCFA的确切作用 在ALD发病机制中的作用，并可能为ALD的表型提供线索 ALD的变异性特征。

The long-term objective of this project is to understand the molecular pathology and pathogenesis of X-linked adrenoleukodystrophy (ALD), a fatal neurodegenerative disorder. Defective peroxisomal activation of very long-chain fatty acids (VLCFA) by very long-chain fatty acyl-CoA synthetase (VLCS) causes elevated VLCFA levels in ALD patients. The product of the gene shown to be defective in ALD (ALDP) is a peroxisomal membrane protein that is a member of the ATP-binding cassette (ABC) membrane Transporter protein family and does not structurally resemble Acyl-CoA synthetases. Although ALDP is clearly required for normal degradation of VLCFA, it does not have VLCS activity, and neither its biochemical function nor its role in ALD have been elucidated. However, mutations in this protein lead to devastating clinical pathology. To develop clinical therapies and to study the pathophysiology of this disease, both genetic and biochemical studies of ALDP function will be used. The VLCS gene will be cloned and its gene product characterized in order to elucidate the relationship of VLCS, previously thought to be the defect in ALD, to ALDP. Two types of mutagenesis strategies, random mutagenesis and disruption of specific regions of the regions of the protein, will be used to analyze the structure and function of ALDP. Because ABC proteins often require interaction with other proteins for function, genetic and biochemical approaches will be used to elucidate ALDP-protein interactions. Finally, the effect of ALDP on VLCFA metabolism in several cell types (including cells of neural origin) and in model membranes will examined. These studies will lead to a better understanding of ALDP function and the precise roles of ALDP and VLCFA in the pathogenesis of ALD and perhaps provide clues for the phenotypic variability characteristic of ALD.