Insights into the role of oxidative stress in the pathology of Friedreich ataxia using peroxidation resistant polyunsaturated fatty acids.
Insights into the role of oxidative stress in the pathology of Friedreich ataxia using peroxidation resistant polyunsaturated fatty acids.
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DOI：
10.1016/j.redox.2013.06.004
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发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Shchepinov MS
中科院分区：
文献类型：
--
作者：
Cotticelli MG;Crabbe AM;Wilson RB;Shchepinov MS
弗里德赖希共济失调是一种常染色体隐性遗传的神经和心脏退行性疾病，其特征为四肢进行性共济失调、构音障碍、反射消失、感觉丧失、骨骼畸形和肥厚性心肌病。大多数疾病等位基因在FXN基因的第一个内含子中具有三核苷酸重复扩增，这降低了编码蛋白共济失调蛋白的表达。Frataxin参与线粒体基质中的铁硫簇（ISC）组装，并且减少的Frataxin与ISC酶和线粒体功能障碍、线粒体铁积累和增加的氧化应激相关。为了评估氧化应激在弗里德赖希共济失调中脂质过氧化作用的作用，我们使用了在双烯丙基位点氘代的多不饱和脂肪酸（PUFA）治疗弗里德赖希共济失调细胞模型的新方法。在ROS驱动的PUFA氧化中，限速步骤是从双烯丙基位点提取氢;双烯丙基位点的同位素强化（氘化）减缓了它们的过氧化。我们发现，亚油酸和α-亚麻酸氘代在过氧化倾向的双烯丙基位置积极拯救氧化应激挑战弗里德赖希共济失调细胞。在我们的模型中，氘代PUFA的保护作用与CoQ 10类似物艾地苯醌的保护作用是相加的，艾地苯醌被认为可以减少自由基的产生。此外，通过脂肪酸类似物C11-BODIPY（581/591）探针的荧光测量，给予氘代PUFA导致脂质过氧化降低。我们的研究结果与Friedreich共济失调病理学中脂质过氧化的作用一致，并表明口服同位素增强PUFA的新方法可能对Friedreich共济失调和其他涉及氧化应激和脂质过氧化的疾病具有治疗潜力。我们在弗里德赖希共济失调的细胞模型中测试氘代多不饱和脂肪酸。亚油酸和α-亚麻酸会加剧这些细胞的氧化应激毒性。氘代亚油酸和α-亚麻酸保护这些细胞免受氧化应激。细胞拯救与脂质过氧化作用降低相关。氘代多不饱和脂肪酸可能是治疗弗里德赖希共济失调的一种药物。
Friedreich ataxia is an autosomal recessive, inherited neuro- and cardio-degenerative disorder characterized by progressive ataxia of all four limbs, dysarthria, areflexia, sensory loss, skeletal deformities, and hypertrophic cardiomyopathy. Most disease alleles have a trinucleotide repeat expansion in the first intron of the FXN gene, which decreases expression of the encoded protein frataxin. Frataxin is involved in iron–sulfur-cluster (ISC) assembly in the mitochondrial matrix, and decreased frataxin is associated with ISC-enzyme and mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. To assess the role of oxidative stress in lipid peroxidation in Friedreich ataxia we used the novel approach of treating Friedreich ataxia cell models with polyunsaturated fatty acids (PUFAs) deuterated at bis-allylic sites. In ROS-driven oxidation of PUFAs, the rate-limiting step is hydrogen abstraction from a bis-allylic site; isotopic reinforcement (deuteration) of bis-allylic sites slows down their peroxidation. We show that linoleic and α-linolenic acids deuterated at the peroxidation-prone bis-allylic positions actively rescue oxidative-stress-challenged Friedreich ataxia cells. The protective effect of the deuterated PUFAs is additive in our models with the protective effect of the CoQ10 analog idebenone, which is thought to decrease the production of free radicals. Moreover, the administration of deuterated PUFAs resulted in decreased lipid peroxidation as measured by the fluorescence of the fatty acid analog C11-BODIPY (581/591) probe. Our results are consistent with a role for lipid peroxidation in Friedreich ataxia pathology, and suggest that the novel approach of oral delivery of isotope-reinforced PUFAs may have therapeutic potential in Friedreich ataxia and other disorders involving oxidative stress and lipid peroxidation. We test deuterated polyunsaturated fatty acids in cell models of Friedreich ataxia. Linoleic and α-linolenic acids exacerbate oxidative-stress toxicity in these cells. Deuterated linoleic and α-linolenic acids protect these cells from oxidative stress. Cell rescue correlates with decreased lipid peroxidation. Deuterated polyunsaturated fatty acids might be a therapeutic for Friedreich ataxia.