Neurometabolic Disease Lab, Institut of Neuropathology, Institut d'Investigació Biomèdica de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
Hum Mol Genet. 2010 May 15;19(10):2005-14. doi: 10.1093/hmg/ddq082. Epub 2010 Feb 23.
X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurometabolic disease. It results from the functional loss of a member of the peroxisomal ATP-binding cassette transporter subfamily D (ABCD1), which is involved in the metabolism of very long-chain fatty acids (VLCFA). Oxidative damage of proteins caused by excess of the hexacosanoic acid, the most prevalent VLCFA accumulating in X-ALD, is an early event in the neurodegenerative cascade. We demonstrate here that valproic acid (VPA), a widely used anti-epileptic drug with histone deacetylase inhibitor properties, induced the expression of the functionally overlapping ABCD2 peroxisomal transporter. VPA corrected the oxidative damage and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of X-ALD. A 6-month pilot trial of VPA in X-ALD patients resulted in reversion of the oxidative damage of proteins in peripheral blood mononuclear cells. Thus, we propose VPA as a promising novel therapeutic approach that warrants further clinical investigation in X-ALD.
X 连锁肾上腺脑白质营养不良（X-ALD）是一种致命的、轴突脱髓鞘的、神经代谢性疾病。它是由于过氧化物酶体 ATP 结合盒转运子亚家族 D（ABCD1）的一个成员功能丧失引起的，该成员参与极长链脂肪酸（VLCFA）的代谢。在神经退行性级联反应的早期，二十六烷酸（X-ALD 中最常见的积累的 VLCFA）引起的蛋白质氧化损伤是一个早期事件。我们在这里证明，丙戊酸（VPA），一种广泛使用的具有组蛋白去乙酰化酶抑制剂特性的抗癫痫药物，诱导功能重叠的 ABCD2 过氧化物酶体转运蛋白的表达。VPA 纠正了氧化损伤并降低了单不饱和 VLCFA（C26:1 n-9）的水平，但不降低饱和 VLCFA。单独过表达 ABCD2 可防止 X-ALD 小鼠模型中蛋白质的氧化损伤。为期 6 个月的 X-ALD 患者 VPA 试验导致外周血单核细胞中蛋白质氧化损伤的逆转。因此，我们提出 VPA 作为一种有前途的新的治疗方法，值得在 X-ALD 中进一步临床研究。
