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G3:肌萎缩性侧索硬化症新治疗靶点

来源:生物谷 2012-07-19 11:48

近日,俄勒冈卫生科学大学牙医学院研究人员发现,TDP-43蛋白质与ALS(肌萎缩性侧索硬化症)和其他神经退行性疾病密切相关,基因操纵该蛋白时会激活各种不同的分子途径。这一发现为治疗ALS和神经退行性疾病如阿尔茨海默氏症和帕金森氏提供了新思路。

肌萎缩性脊髓侧索硬化症(ALS, Amyotrophic lateral sclerosis),又称路格瑞氏症(Lou Gehrig's disease),俗称为渐冻人症,是一个渐进和致命的神经退行性疾病。起因是中枢神经系统内控制骨骼肌的运动神经元(motor neuron)退化所致。

OHSU研究团队利用果蝇模型,基因增加或消除TDP-43,以研究其对中枢神经系统的影响。通过使用大规模并行测序的方法来分析中枢神经系统的基因表达, 研究数据表明,TDP-43在突触传递、突触释放和内吞中起着重要作用。这项研究由国家健康(NS071186)研究院、ALS协会和肌肉萎缩症协会资助。(生物谷:Bioon.com)

Comparison of Parallel High-Throughput RNA Sequencing Between Knockout of TDP-43 and Its Overexpression Reveals Primarily Nonreciprocal and Nonoverlapping Gene Expression Changes in the Central Nervous System of Drosophila

Dennis J. Hazelett, Jer-Cherng Chang, Daniel L. Lakeland and David B. Morton1

The human Tar-DNA binding protein, TDP-43, is associated with amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. TDP-43 contains two conserved RNA-binding motifs and has documented roles in RNA metabolism, including pre-mRNA splicing and repression of transcription. Here, using Drosophila melanogaster as a model, we generated loss-of-function and overexpression genotypes of Tar-DNA binding protein homolog (TBPH) to study their effect on the transcriptome of the central nervous system (CNS). By using massively parallel sequencing methods (RNA-seq) to profile the CNS, we find that loss of TBPH results in widespread gene activation and altered splicing, much of which are reversed by rescue of TBPH expression. Conversely, TBPH overexpression results in decreased gene expression. Although previous studies implicated both absence and mis-expression of TDP-43 in ALS, our data exhibit little overlap in the gene expression between them, suggesting that the bulk of genes affected by TBPH loss-of-function and overexpression are different. In combination with computational approaches to identify likely TBPH targets and orthologs of previously identified vertebrate TDP-43 targets, we provide a comprehensive analysis of enriched gene ontologies. Our data suggest that TDP-43 plays a role in synaptic transmission, synaptic release, and endocytosis. We also uncovered a potential novel regulation of the Wnt and BMP pathways, many of whose targets appear to be conserved. 

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