MicroRNA-277 modulates the neurodegeneration caused by Fragile X premutation rCGG repeats.
MicroRNA-277 modulates the neurodegeneration caused by Fragile X premutation rCGG repeats.
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MicroRNA-277 调节脆性 X 前突变 rCGG 重复序列引起的神经变性
DOI：
10.1371/journal.pgen.1002681
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Jin P
中科院分区：
文献类型：
--
作者：
Tan H;Poidevin M;Li H;Chen D;Jin P
脆性X相关震颤/共济失调综合征(FXTAS)是一种迟发的神经退行性疾病，已在老年男性脆性X预突变携带者中被发现，并与脆性X综合征脱钩。使用FXTAS的果蝇模型，我们之前证明了仅转录前突变重复就足以导致神经退化。MiRNAs是转录后基因表达的序列特异性调节因子。为了确定miRNAs在rCGG重复序列介导的神经变性中的作用，我们分析了miRNA的表达情况，并确定了选择性miRNAs，包括miR-277，这些miRNAs在表达rCGG重复序列的果蝇脑中特异性地改变。我们测试了它们与rCGG重复序列的遗传交互作用，发现miR-277可以调节rCGG重复序列介导的神经退行性变。此外，我们发现DREP-2和VIMAR是miR-277的功能靶点，可以调节rCGG重复序列介导的神经退行性变。最后，我们发现rCGG重复结合蛋白hnRNP A2/B1可以直接调控miR-277的表达。这些结果表明，特定的rCGG重复结合蛋白可以导致选择性miRNAs的异常表达，这可能通过转录后调节参与FXTAS的特定mRNAs的表达来调节FXTAS的发病。
Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder, has been recognized in older male fragile X premutation carriers and is uncoupled from fragile X syndrome. Using a Drosophila model of FXTAS, we previously showed that transcribed premutation repeats alone are sufficient to cause neurodegeneration. MiRNAs are sequence-specific regulators of post-transcriptional gene expression. To determine the role of miRNAs in rCGG repeat-mediated neurodegeneration, we profiled miRNA expression and identified selective miRNAs, including miR-277, that are altered specifically in Drosophila brains expressing rCGG repeats. We tested their genetic interactions with rCGG repeats and found that miR-277 can modulate rCGG repeat-mediated neurodegeneration. Furthermore, we identified Drep-2 and Vimar as functional targets of miR-277 that could modulate rCGG repeat-mediated neurodegeneration. Finally, we found that hnRNP A2/B1, an rCGG repeat-binding protein, can directly regulate the expression of miR-277. These results suggest that sequestration of specific rCGG repeat-binding proteins could lead to aberrant expression of selective miRNAs, which may modulate the pathogenesis of FXTAS by post-transcriptionally regulating the expression of specific mRNAs involved in FXTAS.
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影响因子：
56.9
作者：
Kim, Jongpil;Inoue, Keiichi;Abeliovich, Asa
通讯作者：
Abeliovich, Asa
影响因子：
64.5
作者：
FU, YH;KUHL, DPA;CASKEY, CT
通讯作者：
CASKEY, CT
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart
影响因子：
3.5
作者：
Hashem, Vera;Galloway, Jocelyn N.;Nelson, David L.
通讯作者：
Nelson, David L.
影响因子：
3.5
作者：
Arocena, DG;Iwahashi, CK;Hagerman, PJ
通讯作者：
Hagerman, PJ