N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice
N-acetyl Cysteine Treatment Rescues Cognitive Deficits Induced by Mitochondrial Dysfunction in G72/G30 Transgenic Mice
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DOI：
10.1038/npp.2011.109
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发表时间：
2011-06
影响因子：
7.6
通讯作者：
D. Otte;B. Sommersberg;A. Kudin;Catalina Guerrero;Önder Albayram;M. Filiou;Pamela Frisch;Öznur Yilmaz;E. Drews;C. Turck;A. Bilkei-Gorzo;W. Kunz;H. Beck;A. Zimmer
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文献类型：
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作者：
D. Otte;B. Sommersberg;A. Kudin;Catalina Guerrero;Önder Albayram;M. Filiou;Pamela Frisch;Öznur Yilmaz;E. Drews;C. Turck;A. Bilkei-Gorzo;W. Kunz;H. Beck;A. Zimmer
遗传学研究表明，进化新的灵长类特异性基因位点G72/G30与精神疾病有关。该基因编码蛋白LG 72，其已被讨论为作为过氧化物酶体酶D-氨基酸氧化酶（DAO）的推定激活剂和作为线粒体蛋白发挥作用。我们最近产生了“人源化”细菌人工染色体转基因小鼠（G72 Tg），在整个大脑的细胞中表达G72转录本。这些小鼠表现出与精神疾病相关的几种行为表型。在这里，我们表明，G72 Tg小鼠具有线粒体复合物I的活性降低，伴随着活性氧的产生增加。受影响的神经元表现出短期可塑性缺陷和维持突触活动的能力受损。这些缺陷导致空间记忆障碍，可以通过谷胱甘肽前体N-乙酰半胱氨酸的药物治疗来挽救。我们的研究结果暗示LG 72诱导的线粒体和突触缺陷是精神疾病的一种可能的病理机制。
Genetic studies have implicated the evolutionary novel, anthropoid primate-specific gene locus G72/G30 in psychiatric diseases. This gene encodes the protein LG72 that has been discussed to function as a putative activator of the peroxisomal enzyme D-amino-acid-oxidase (DAO) and as a mitochondrial protein. We recently generated ‘humanized’bacterial artificial chromosome transgenic mice (G72Tg) expressing G72 transcripts in cells throughout the brain. These mice exhibit several behavioral phenotypes related to psychiatric diseases. Here we show that G72Tg mice have a reduced activity of mitochondrial complex I, with a concomitantly increased production of reactive oxygen species. Affected neurons display deficits in short-term plasticity and an impaired capability to sustain synaptic activity. These deficits lead to an impairment in spatial memory, which can be rescued by pharmacological treatment with the glutathione precursor N-acetyl cysteine. Our results implicate LG72-induced mitochondrial and synaptic defects as a possible pathomechanism of psychiatric disorders.