肾上腺脑白质营养不良模型系统的演变。
Evolution of adrenoleukodystrophy model systems.
机构信息
Department of Pediatric Neurology, Emma Children's Hospital, Amsterdam UMC, Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, The Netherlands.
Department of Child and Youth Psychiatry, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
出版信息
J Inherit Metab Dis. 2021 May;44(3):544-553. doi: 10.1002/jimd.12357. Epub 2021 Jan 7.
X-linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the ABCD1 gene resulting in a defect in peroxisomal degradation of very long-chain fatty acids and their accumulation in plasma and tissues. Males with ALD have a near 100% life-time risk to develop myelopathy. The life-time prevalence to develop progressive cerebral white matter lesions (known as cerebral ALD) is about 60%. Adrenal insufficiency occurs in about 80% of male patients. In adulthood, 80% of women with ALD also develop myelopathy, but adrenal insufficiency or cerebral ALD are very rare. The complex clinical presentation and the absence of a genotype-phenotype correlation are complicating our understanding of the disease. In an attempt to understand the pathophysiology of ALD various model systems have been developed. While these model systems share the basic genetics and biochemistry of ALD they fail to fully recapitulate the complex neurodegenerative etiology of ALD. Each model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single-celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC-derived technologies could improve the understanding of this highly complex disorder.
X 连锁肾上腺脑白质营养不良(ALD)是一种影响肾上腺、睾丸、脊髓和大脑的神经代谢疾病。该疾病是由 ABCD1 基因突变引起的,导致过氧化物酶体降解极长链脂肪酸的缺陷和它们在血浆和组织中的积累。ALD 男性患者几乎有 100%的终生风险发展为脊髓病。大约 60%的患者会终生发展为进行性脑白质病变(称为脑 ALD)。大约 80%的男性患者会出现肾上腺功能不全。在成年期,80%的女性 ALD 患者也会发展为脊髓病,但肾上腺功能不全或脑 ALD 非常罕见。复杂的临床表现和基因型-表型相关性的缺乏使我们对该疾病的理解变得复杂。为了了解 ALD 的病理生理学,已经开发了各种模型系统。虽然这些模型系统具有 ALD 的基本遗传学和生物化学特征,但它们不能完全再现 ALD 复杂的神经退行性病因。每个模型系统都能再现疾病的某些方面。这暴露了 ALD 的复杂性,因此创建一个全面的模型系统来全面了解 ALD 是一个挑战。在这篇综述中,我们概述了从单细胞到多细胞生物以及从体外到体内方法的不同 ALD 建模策略,并介绍了新兴的 iPSC 衍生技术如何改善对这种高度复杂疾病的理解。
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