Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay
Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay
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DOI：
10.1007/s00415-015-7911-4
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发表时间：
2015-12-01
影响因子：
6
通讯作者：
Santorelli, F. M.
中科院分区：
文献类型：
--
作者：
Criscuolo, Chiara;Procaccini, C.;Santorelli, F. M.
常染色体隐性痉挛性共济失调（ARSACS）是一种由SACS突变引起的神经退行性疾病，SACS编码sacin， sacin是一种定位于线粒体表面的蛋白质，可能参与线粒体动力学。鉴于sacsin可能与线粒体有关，我们在ARSACS患者皮肤成纤维细胞的功能和分子水平上研究了线粒体活性。我们观察到ARSACS细胞明显的生物能量损伤，如基础、三磷酸腺苷（ATP）连接和最大线粒体呼吸速率降低，呼吸链活性和线粒体ATP合成降低。这些现象与活性氧产生增加和核DNA氧化损伤有关。我们的研究结果表明，sacin的丢失与氧化应激和线粒体功能障碍有关，从而强调了ARSACS发病的新机制。线粒体和氧化应激在疾病发病机制中的参与已在许多其他神经退行性疾病中得到描述。因此，根据我们的研究结果，这表明抗氧化剂具有潜在的治疗作用，ARSACS似乎属于更大的疾病群体。
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.