Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain.
Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain.
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DOI：
10.1371/journal.pone.0082685
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Karten B
中科院分区：
文献类型：
--
作者：
Kennedy BE;LeBlanc VG;Mailman TM;Fice D;Burton I;Karakach TK;Karten B
C型尼曼-皮克病（NPC）是一种常染色体隐性遗传神经退行性疾病，大多数情况下由NPC 1基因突变引起。NPC 1缺陷的特征在于胆固醇的晚期内体积累、胆固醇稳态受损和广泛的其他细胞异常。虽然在大脑的几乎所有区域都观察到神经元异常和神经胶质活化，但NPC 1缺陷的最严重后果是小脑中浦肯野神经元几乎完全丧失。胆固醇运输和NPC发病机制之间的联系尚不清楚;然而，有症状的NPC疾病中氧化应激增加，线粒体胆固醇增加和自噬/线粒体自噬的改变表明线粒体在NPC疾病病理学中起作用。线粒体功能的改变会影响能量和神经递质的代谢，对中枢神经系统尤其有害。为了研究可能影响NPC疾病进展的早期代谢改变，我们通过1H-NMR光谱对年龄匹配的野生型和Npc 1-/-小鼠在症状前、早期症状和晚期疾病的不同脑区进行了代谢组学分析。代谢分析显示，在所有年龄组的Npc 1-/-小脑和大脑皮层中，乳酸盐显著增加，乙酸盐/乙酰辅酶A水平降低。蛋白质和基因表达分析表明，症状前丙酮酸氧化脱羧乙酰辅酶A的缺陷，和糖酵解基因表达的上调在早期症状阶段。我们还观察到Npc 1-/-小脑中氧化应激和抗氧化反应系统的几个指标的症状前增加。我们的研究结果表明，能量代谢和氧化应激可能是NPC疾病的额外治疗靶点，特别是如果可以在疾病的早期阶段开始干预。
Niemann-Pick Type C (NPC) disease is an autosomal recessive neurodegenerative disorder caused in most cases by mutations in the NPC1 gene. NPC1-deficiency is characterized by late endosomal accumulation of cholesterol, impaired cholesterol homeostasis, and a broad range of other cellular abnormalities. Although neuronal abnormalities and glial activation are observed in nearly all areas of the brain, the most severe consequence of NPC1-deficiency is a near complete loss of Purkinje neurons in the cerebellum. The link between cholesterol trafficking and NPC pathogenesis is not yet clear; however, increased oxidative stress in symptomatic NPC disease, increases in mitochondrial cholesterol, and alterations in autophagy/mitophagy suggest that mitochondria play a role in NPC disease pathology. Alterations in mitochondrial function affect energy and neurotransmitter metabolism, and are particularly harmful to the central nervous system. To investigate early metabolic alterations that could affect NPC disease progression, we performed metabolomics analyses of different brain regions from age-matched wildtype and Npc1 -/- mice at pre-symptomatic, early symptomatic and late stage disease by 1H-NMR spectroscopy. Metabolic profiling revealed markedly increased lactate and decreased acetate/acetyl-CoA levels in Npc1 -/- cerebellum and cerebral cortex at all ages. Protein and gene expression analyses indicated a pre-symptomatic deficiency in the oxidative decarboxylation of pyruvate to acetyl-CoA, and an upregulation of glycolytic gene expression at the early symptomatic stage. We also observed a pre-symptomatic increase in several indicators of oxidative stress and antioxidant response systems in Npc1 -/- cerebellum. Our findings suggest that energy metabolism and oxidative stress may present additional therapeutic targets in NPC disease, especially if intervention can be started at an early stage of the disease.
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发表时间：
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DOI：
10.1523/jneurosci.1317-11.2011
发表时间：
2011-06-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
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