Transcriptome Analysis of the Human Striatum in Tourette Syndrome.
Transcriptome Analysis of the Human Striatum in Tourette Syndrome.
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DOI：
10.1016/j.biopsych.2014.07.018
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发表时间：
2016-03-01
影响因子：
10.6
通讯作者：
Vaccarino FM
中科院分区：
文献类型：
--
作者：
Lennington JB;Coppola G;Kataoka-Sasaki Y;Fernandez TV;Palejev D;Li Y;Huttner A;Pletikos M;Sestan N;Leckman JF;Vaccarino FM
全基因组关联研究尚未发现任何风险赋予的常见遗传变异的抽动秽语综合征（TS），需要采用替代方法来研究这种疾病的病理生理学。我们通过9例TS和9例匹配的正常对照的尾状核和壳核的RNA测序获得了基底神经节转录组。我们发现309下调和822上调基因的尾状核和壳核（纹状体）的TS个人。使用数据驱动的基因网络分析，我们确定了17个与TS相关的基因共表达模块。TS中得分最高的下调模块在纹状体中间神经元转录物中富集，这通过相同区域中的胆碱能和GABA能中间神经元的数量减少来证实。得分最高的上调模块富含免疫相关基因，与患者纹状体中小胶质细胞的激活一致。TS中拷贝数变异（CNV）所涉及的基因在中间神经元模块和原钙粘蛋白模块中富集。模块聚类显示，中间神经元模块与神经元代谢模块相关。差异表达、网络分析和模块聚类的融合，以及TS中涉及的CNV，强烈暗示了严重TS病理生理学中的中断的中间神经元信号传导，并表明代谢改变可能与其死亡或功能障碍有关。
Genome wide association studies have not revealed any risk-conferring common genetic variants in Tourette syndrome (TS), requiring the adoption of alternative approaches to investigate the pathophysiology of this disorder. We obtained the basal ganglia transcriptome by RNA sequencing in the caudate and putamen of 9 TS and 9 matched normal controls. We found 309 down-regulated and 822 up-regulated genes in the caudate and putamen (striatum) of TS individuals. Using data-driven gene network analysis, we identified seventeen gene co-expression modules associated with TS. The top-scoring down-regulated module in TS was enriched in striatal interneuron transcripts, which was confirmed by decreased numbers of cholinergic and GABAergic interneurons by immunohistochemistry in the same regions. The top-scoring up-regulated module was enriched in immune-related genes, consistent with activation of microglia in patients’ striatum. Genes implicated by copy number variants (CNV) in TS were enriched in the interneuron module as well as in a protocadherin module. Module clustering revealed that the interneuron module was correlated with a neuronal metabolism module. Convergence of differential expression, network analyses and module clustering, together with CNVs implicated in TS, strongly implicates disrupted interneuron signaling in the pathophysiology of severe TS, and suggests that metabolic alterations may be linked to their death or dysfunction.
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影响因子：
5.3
作者：
Goldberg, EM;Watanabe, S;Rudy, B
通讯作者：
Rudy, B
DOI：
10.1002/cne.22206
发表时间：
2010-02-01
期刊：
The Journal of comparative neurology
影响因子：
--
作者：
Kataoka Y;Kalanithi PS;Grantz H;Schwartz ML;Saper C;Leckman JF;Vaccarino FM
通讯作者：
Vaccarino FM
DOI：
10.1523/jneurosci.4870-09.2010
发表时间：
2010-02-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gittis AH;Nelson AB;Thwin MT;Palop JJ;Kreitzer AC
通讯作者：
Kreitzer AC
DOI：
10.1523/jneurosci.3875-11.2011
发表时间：
2011-11-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Gittis AH;Leventhal DK;Fensterheim BA;Pettibone JR;Berke JD;Kreitzer AC
通讯作者：
Kreitzer AC
影响因子：
2.9
作者：
FigueredoCardenas, G;Morello, M;Reiner, A
通讯作者：
Reiner, A