脆性X智力低下蛋白在调节PSD-95 mRNA稳定性方面的新功能。
A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability.
作者信息
Zalfa Francesca, Eleuteri Boris, Dickson Kirsten S, Mercaldo Valentina, De Rubeis Silvia, di Penta Alessandra, Tabolacci Elisabetta, Chiurazzi Pietro, Neri Giovanni, Grant Seth G N, Bagni Claudia
机构信息
Dipartimento di Biologia, Università Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy.
出版信息
Nat Neurosci. 2007 May;10(5):578-87. doi: 10.1038/nn1893. Epub 2007 Apr 8.
Abstract
Fragile X syndrome (FXS) results from the loss of the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates a variety of cytoplasmic mRNAs. FMRP regulates mRNA translation and may be important in mRNA localization to dendrites. We report a third cytoplasmic regulatory function for FMRP: control of mRNA stability. In mice, we found that FMRP binds, in vivo, the mRNA encoding PSD-95, a key molecule that regulates neuronal synaptic signaling and learning. This interaction occurs through the 3' untranslated region of the PSD-95 (also known as Dlg4) mRNA, increasing message stability. Moreover, stabilization is further increased by mGluR activation. Although we also found that the PSD-95 mRNA is synaptically localized in vivo, localization occurs independently of FMRP. Through our functional analysis of this FMRP target we provide evidence that dysregulation of mRNA stability may contribute to the cognitive impairments in individuals with FXS.
摘要
脆性X综合征（FXS）是由于脆性X智力低下蛋白（FMRP）缺失所致，FMRP是一种调节多种细胞质mRNA的RNA结合蛋白。FMRP调节mRNA翻译，并且在mRNA定位于树突方面可能起重要作用。我们报告了FMRP的第三种细胞质调节功能：控制mRNA稳定性。在小鼠中，我们发现FMRP在体内与编码PSD-95的mRNA结合，PSD-95是一种调节神经元突触信号传导和学习的关键分子。这种相互作用通过PSD-95（也称为Dlg4）mRNA的3'非翻译区发生，增加了mRNA的稳定性。此外，mGluR激活可进一步增强稳定性。虽然我们还发现PSD-95 mRNA在体内定位于突触，但定位独立于FMRP发生。通过对这个FMRP靶点的功能分析，我们提供了证据表明mRNA稳定性失调可能导致FXS患者的认知障碍。
相似文献
1
A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability.脆性X智力低下蛋白在调节PSD-95 mRNA稳定性方面的新功能。
Nat Neurosci. 2007 May;10(5):578-87. doi: 10.1038/nn1893. Epub 2007 Apr 8.
2
Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome.在脆性X综合征小鼠模型中，代谢型谷氨酸受体依赖性的AMPA受体和突触后致密蛋白95 mRNA在突触处的翻译失调。
J Neurosci. 2007 May 16;27(20):5338-48. doi: 10.1523/JNEUROSCI.0937-07.2007.
3
Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling.miR-125a、FMRP 磷酸化和 mGluR 信号对 PSD-95 mRNA 翻译的可逆抑制作用。
Mol Cell. 2011 Jun 10;42(5):673-88. doi: 10.1016/j.molcel.2011.05.006.
4
Fragile X mental retardation protein regulates the levels of scaffold proteins and glutamate receptors in postsynaptic densities.脆性X智力低下蛋白调节突触后致密物中支架蛋白和谷氨酸受体的水平。
J Biol Chem. 2009 Sep 18;284(38):25479-87. doi: 10.1074/jbc.M109.042663. Epub 2009 Jul 28.
5
Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation.树突中去磷酸化诱导的 FMRP 泛素化和降解：在即时早期 mGluR 刺激的翻译中的作用。
J Neurosci. 2012 Feb 22;32(8):2582-7. doi: 10.1523/JNEUROSCI.5057-11.2012.
6
Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome.脆性X综合征小鼠模型中树突内PSD - 95 mRNA翻译的单分子成像及其失调
J Neurosci. 2015 May 6;35(18):7116-30. doi: 10.1523/JNEUROSCI.2802-14.2015.
7
The fragile X mental retardation protein-RNP granules show an mGluR-dependent localization in the post-synaptic spines.脆性X智力低下蛋白核糖核蛋白颗粒在突触后棘中表现出一种代谢型谷氨酸受体依赖性定位。
Mol Cell Neurosci. 2007 Mar;34(3):343-54. doi: 10.1016/j.mcn.2006.11.015. Epub 2007 Jan 23.
8
The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95.脆性X智力低下蛋白是PSD-95的I型代谢型谷氨酸受体依赖性翻译所必需的。
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14374-8. doi: 10.1073/pnas.2336265100. Epub 2003 Nov 12.
9
Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome.脆性 X 综合征中过量的磷酯酰肌醇 3-激酶亚基合成和活性作为一种新的治疗靶点。
J Neurosci. 2010 Aug 11;30(32):10624-38. doi: 10.1523/JNEUROSCI.0402-10.2010.
10
Visual-spatial learning impairments are associated with hippocampal PSD-95 protein dysregulation in a mouse model of fragile X syndrome.在脆性X综合征小鼠模型中，视觉空间学习障碍与海马体中突触后密度蛋白95（PSD-95）的蛋白失调有关。
Neuroreport. 2014 Mar 5;25(4):255-61. doi: 10.1097/WNR.0000000000000087.
引用本文的文献
1
Conditional deletion of TRPC1 channel modulates synaptic plasticity, long term depression, and memory extinction in Fragile X syndrome mice.TRPC1通道的条件性缺失调节脆性X综合征小鼠的突触可塑性、长期抑郁和记忆消退。
iScience. 2025 Jul 10;28(8):113085. doi: 10.1016/j.isci.2025.113085. eCollection 2025 Aug 15.
2
Loss of FMRP in microglia promotes degeneration of parvalbumin neurons and audiogenic seizures via progranulin insufficiency.小胶质细胞中FMRP的缺失通过颗粒前体蛋白不足促进小白蛋白神经元变性和听源性癫痫发作。
bioRxiv. 2025 Jul 12:2025.07.09.663876. doi: 10.1101/2025.07.09.663876.
3
TAS-seq enables subcellular single-stranded adenosine profiling by signal peptide-assisted adenosine deamination.TAS-seq通过信号肽辅助的腺苷脱氨作用实现亚细胞单链腺苷分析。
Cell Rep Methods. 2025 Jul 21;5(7):101087. doi: 10.1016/j.crmeth.2025.101087. Epub 2025 Jun 25.
4
CA1 Pyramidal Neurons Exhibit Upregulated Translation of Long MRNAs Associated with LTP.CA1锥体神经元表现出与长时程增强相关的长链mRNA翻译上调。
eNeuro. 2025 May 19;12(5). doi: 10.1523/ENEURO.0086-25.2025. Print 2025 May.
5
CircRNA hsa_circ_0004781 promoted cell proliferation by acting as a sponge for miR-9-5p and miR-338-3p and upregulating KLF5 and ADAM17 expression in pancreatic ductal adenocarcinoma.环状RNA hsa_circ_0004781通过作为miR-9-5p和miR-338-3p的海绵，上调胰腺导管腺癌中KLF5和ADAM17的表达，从而促进细胞增殖。
Cancer Cell Int. 2025 Feb 19;25(1):56. doi: 10.1186/s12935-025-03687-0.
6
Transcriptomics analysis reveals potential regulatory role of nSMase2 (Smpd3) in nervous system development and function of middle-aged mouse brains.转录组学分析揭示了 nSMase2（Smpd3）在中年小鼠大脑神经系统发育和功能中的潜在调节作用。
Genes Brain Behav. 2024 Aug;23(4):e12911. doi: 10.1111/gbb.12911.
7
Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model.星形胶质细胞 Kir4.1 钾通道缺陷导致脆性 X 综合征小鼠模型中的神经元过度兴奋和行为缺陷。
Nat Commun. 2024 Apr 27;15(1):3583. doi: 10.1038/s41467-024-47681-y.
8
FMR1 Protein Expression Correlates with Intelligence Quotient in Both Peripheral Blood Mononuclear Cells and Fibroblasts from Individuals with an FMR1 Mutation.脆性 X 智力低下 1 号蛋白（FMR1）在突变个体的外周血单个核细胞和成纤维细胞中的表达与智商相关。
J Mol Diagn. 2024 Jun;26(6):498-509. doi: 10.1016/j.jmoldx.2024.02.007. Epub 2024 Mar 22.
9
Translational modulator ISRIB alleviates synaptic and behavioral phenotypes in Fragile X syndrome.翻译调节剂ISRIB可缓解脆性X综合征中的突触和行为表型。
iScience. 2024 Feb 16;27(4):109259. doi: 10.1016/j.isci.2024.109259. eCollection 2024 Apr 19.
10
The intersection of sleep and synaptic translation in synaptic plasticity deficits in neurodevelopmental disorders.睡眠与突触翻译在神经发育障碍突触可塑性缺陷中的交汇
J Comp Physiol B. 2024 Jun;194(3):253-263. doi: 10.1007/s00360-023-01531-3. Epub 2024 Feb 24.
本文引用的文献
1
Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies.突触相关蛋白102/dlgh3将NMDA受体与特定的可塑性通路和学习策略相耦合。
J Neurosci. 2007 Mar 7;27(10):2673-82. doi: 10.1523/JNEUROSCI.4457-06.2007.
2
Repression of protein synthesis by miRNAs: how many mechanisms?微小RNA对蛋白质合成的抑制作用：有多少种机制？
Trends Cell Biol. 2007 Mar;17(3):118-26. doi: 10.1016/j.tcb.2006.12.007. Epub 2007 Jan 2.
3
Genome-wide atlas of gene expression in the adult mouse brain.成年小鼠大脑基因表达的全基因组图谱。
Nature. 2007 Jan 11;445(7124):168-76. doi: 10.1038/nature05453. Epub 2006 Dec 6.
4
Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories.Arc/Arg3.1对于突触可塑性和记忆的巩固至关重要。
Neuron. 2006 Nov 9;52(3):437-44. doi: 10.1016/j.neuron.2006.08.024.
5
mRNPs, polysomes or granules: FMRP in neuronal protein synthesis.信使核糖核蛋白颗粒、多聚核糖体或颗粒：神经元蛋白质合成中的脆性X智力低下蛋白（FMRP）
Curr Opin Neurobiol. 2006 Jun;16(3):265-9. doi: 10.1016/j.conb.2006.05.010. Epub 2006 May 16.
6
Neurone specific regulation of dendritic spines in vivo by post synaptic density 95 protein (PSD-95).突触后致密蛋白95（PSD-95）在体内对树突棘的神经元特异性调节。
Brain Res. 2006 May 23;1090(1):89-98. doi: 10.1016/j.brainres.2006.03.075. Epub 2006 May 4.
7
Role of Pur alpha in targeting mRNA to sites of translation in hippocampal neuronal dendrites.Pur alpha在将mRNA靶向海马神经元树突中的翻译位点方面的作用。
J Neurosci Res. 2006 May 1;83(6):929-43. doi: 10.1002/jnr.20806.
8
RNA binding proteins and the regulation of neuronal synaptic plasticity.RNA结合蛋白与神经元突触可塑性的调控
Curr Opin Neurobiol. 2006 Feb;16(1):102-10. doi: 10.1016/j.conb.2006.01.003. Epub 2006 Jan 18.
9
AU-rich elements and associated factors: are there unifying principles?富含AU元件及其相关因子：是否存在统一的原则？
Nucleic Acids Res. 2006 Jan 3;33(22):7138-50. doi: 10.1093/nar/gki1012. Print 2005.
10
NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder.精神分裂症和心境障碍患者海马体及眶额皮质中N-甲基-D-天冬氨酸（NMDA）受体亚基NRI和突触后蛋白PSD-95
Schizophr Res. 2005 Dec 15;80(2-3):323-30. doi: 10.1016/j.schres.2005.07.003. Epub 2005 Sep 2.
Zotero 插件