MOLECULAR PATHOLOGY AND PATHOGENESIS OF X-ADRENOLEUKODYSTROPHY

该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）的病理学和发病机制， 致命的神经退行性疾病 过氧化物酶体激活缺陷 极长链脂肪酸（VLCFA）通过极长链脂肪酰辅酶A 合成酶（VLCS）引起ALD患者中VLCFA水平升高。 的 ALD（ALDP）缺陷基因的产物是过氧化物酶体 ATP结合盒（ABC）成员的膜蛋白 膜转运蛋白家族，并且在结构上不类似 酰基辅酶A合成酶。 虽然ALDP是明确要求正常 由于VLCFA的降解，它不具有VLCS活性， 生化功能及其在ALD中的作用已经阐明。 然而，在这方面， 这种蛋白质的突变导致毁灭性的临床病理学。 到 开发临床治疗方法，并研究这种疾病的病理生理学， 疾病，ALDP功能的遗传和生物化学研究将是 采用 VLCS基因将被克隆，其基因产物将被表征 为了阐明VLCS的关系，以前认为是 ALD的缺陷转化为ALDP。 两种类型的诱变策略，随机 突变和破坏的区域的特定区域的区域， 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， 功能，遗传和生物化学方法将用于阐明 ALDP-蛋白质相互作用。 最后，研究了ALDP对VLCFA的影响 几种细胞类型（包括神经源细胞）的代谢， 在模型膜将检查。 这些研究将导致更好的 了解ALDP功能以及ALDP和VLCFA的确切作用 在ALD发病机制中的作用，并可能为表型 ALD的可变性特征。

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.