Thiamine Deficiency-Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3.1.
Thiamine Deficiency-Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3.1.
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DOI：
10.1111/bpa.12188
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Giulivi C
中科院分区：
文献类型：
--
作者：
Vernau K;Napoli E;Wong S;Ross-Inta C;Cameron J;Bannasch D;Bollen A;Dickinson P;Giulivi C
阿拉斯加哈士奇脑病（Alaskan Husky encephalopathy，AHE 1）是一种与SLC19A3.1（c.624insTTGC，c.625C>A）突变相关的致死性脑部疾病。该基因编码硫胺素转运蛋白2，主要分布于中枢神经系统（CNS）。考虑到大脑是特别容易受到硫胺素缺乏症，由于其依赖于TPP依赖的代谢途径参与能量代谢和神经递质的合成，我们的特点是这种突变对硫胺素状态的影响，大脑生物能量学，和氧化应激对这种表型的贡献。突变转运蛋白的计算机模拟表明α-螺旋的显著损失，导致更开放的蛋白质结构，表明硫胺素转运能力受损。受影响的狗的大脑皮层和丘脑的TPP依赖性酶严重不足，伴随着线粒体质量和OXPHOS能力的下降，并增加氧化应激。这些结果沿着行为和病理学发现表明，与AHE相关的表型与脑特异性硫胺素缺乏一致，导致脑线粒体功能障碍和氧化应激增加。虽然AHE中的一些生化缺陷、神经行为和受影响的脑区与Wernicke综合征和Korsakoff综合征相同，但注意到可能由组织特异性与全身硫胺素缺乏引起的几个差异。
Alaskan Husky encephalopathy (AHE1) is a fatal brain disease associated with a mutation in SLC19A3.1 (c.624insTTGC, c.625C>A). This gene encodes for a thiamine transporter 2 with a predominantely central nervous system (CNS) distribution. Considering that brain is particularly vulnerable to thiamine deficiency due to its reliance on TPP-dependent metabolic pathways involved in energy metabolism and neurotransmitter synthesis, we characterized the impact of this mutation on thiamine status, brain bioenergetics, and the contribution of oxidative stress to this phenotype. In silico modeling of the mutated transporter indicated a significant loss of alpha-helices resulting in a more open protein structure suggesting an impaired thiamine transport ability. The cerebral cortex and thalamus of affected dogs were severely deficient in TPP-dependent enzymes accompanied by decreases in mitochondrial mass and OXPHOS capacity, and increases in oxidative stress. These results along with the behavioral and pathological findings indicate that the phenotype associated with AHE is consistent with a brain-specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress. While some of the biochemical deficits, neurobehavior and affected brain areas in AHE were shared by Wernicke's and Korsakoff's syndromes, several differences were noted likely arising from a tissue-specific vs. that from a whole-body thiamine deficiency.
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影响因子：
2.5
作者：
Azevedo, Frederico A. C.;Carvalho, Ludmila R. B.;Herculano-Houzel, Suzana
通讯作者：
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DOI：
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发表时间：
1999-09-01
影响因子：
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作者：
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影响因子：
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作者：
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