A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome.
A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome.
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DOI：
10.1093/hmg/ddr251
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发表时间：
2011-09
影响因子：
3.5
通讯作者：
Jie Ren;A. Jegga;Minlu Zhang;Jingyuan Deng;Junbo Liu;Christopher B. Gordon;B. Aronow;L. Lu;Bo Zhang;Jun Ma
中科院分区：
文献类型：
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作者：
Jie Ren;A. Jegga;Minlu Zhang;Jingyuan Deng;Junbo Liu;Christopher B. Gordon;B. Aronow;L. Lu;Bo Zhang;Jun Ma
人类TATA盒结合蛋白(HTBP)中扩展的聚谷氨酰胺(PolyQ)链可导致神经退行性疾病脊髓小脑性共济失调17(SCA17)。为了研究多聚Q扩张的病理效应，我们在果蝇中建立了SCA17模型。与SCA17患者类似，表达突变的hTBP蛋白并带有扩展的PolyQ束(HTBP80Q)的转基因果蝇表现出进行性神经退行性变、迟发性运动障碍和寿命缩短。基因芯片分析表明，hTBP80Q在果蝇中引起广泛的和时间依赖的转录失调。在对遗传修饰物的候选筛选中，我们确定了RBP-J/SU(H)，一个包含Q/N富含结构域的转录因子，参与Notch信号转导。RNAi下调SU(H)进一步增强hTBP80Q诱导的眼缺陷，而过表达SU(H)则抑制这种缺陷。虽然在表达hTBP80Q的果蝇中，SU(H)转录水平没有显著变化，但包含SU(H)结合位点的基因是调控失调的基因之一。我们进一步表明，hTBP80Q与SU(H)的相互作用比野生型hTBP更有效，这表明其正常细胞功能所需的SU(H)比例的减少有助于hTBP80Q诱导的表型。虽然Notch信号通路与多种神经系统疾病有关，但我们的研究表明，其核成分RBP-J/SU(H)的活性可能调节SCA17患者的病理进程。
Expanded polyglutamine (polyQ) tract in the human TATA-box-binding protein (hTBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). To investigate the pathological effects of polyQ expansion, we established a SCA17 model in Drosophila. Similar to SCA17 patients, transgenic flies expressing a mutant hTBP protein with an expanded polyQ tract (hTBP80Q) exhibit progressive neurodegeneration, late-onset locomotor impairment and shortened lifespan. Microarray analysis reveals that hTBP80Q causes widespread and time-dependent transcriptional dysregulation in Drosophila. In a candidate screen for genetic modifiers, we identified RBP-J/Su(H), a transcription factor that contains Q/N-rich domains and participates in Notch signaling. Knockdown of Su(H) by RNAi further enhances hTBP80Q-induced eye defects, whereas overexpression of Su(H) suppresses such defects. While the Su(H) transcript level is not significantly altered in hTBP80Q-expressing flies, genes that contain Su(H)-binding sites are among those that are dysregulated. We further show that hTBP80Q interacts more efficiently with Su(H) than wild-type hTBP, suggesting that a reduction in the fraction of Su(H) available for its normal cellular functions contributes to hTBP80Q-induced phenotypes. While the Notch signaling pathway has been implicated in several neurological disorders, our study suggests a possibility that the activity of its nuclear component RBP-J/Su(H) may modulate the pathological progression in SCA17 patients.