脆性 X 症的病理生理学（及其对突触的启示）。
The pathophysiology of fragile X (and what it teaches us about synapses).
机构信息
Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
出版信息
Annu Rev Neurosci. 2012;35:417-43. doi: 10.1146/annurev-neuro-060909-153138. Epub 2012 Apr 5.
Abstract
Fragile X is the most common known inherited cause of intellectual disability and autism, and it typically results from transcriptional silencing of FMR1 and loss of the encoded protein, FMRP (fragile X mental retardation protein). FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5. Recent studies on the biology of FMRP and the signaling pathways downstream of mGluR1/5 have yielded deeper insight into how synaptic protein synthesis and plasticity are regulated by experience. This new knowledge has also suggested ways that altered signaling and synaptic function can be corrected in fragile X, and human clinical trials based on this information are under way.
摘要
脆性 X 是最常见的已知遗传性智力障碍和自闭症病因，通常由 FMR1 的转录沉默和其编码蛋白 FMRP（脆性 X 智力低下蛋白）缺失导致。FMRP 是一种 mRNA 结合蛋白，在许多突触处发挥作用，抑制代谢型谷氨酸受体 (mGluR) 1 和 5 刺激的局部翻译。最近关于 FMRP 的生物学和 mGluR1/5 下游信号通路的研究深入了解了经验如何调节突触蛋白合成和可塑性。这些新知识还提示了如何纠正脆性 X 中的信号转导和突触功能异常，并且基于这些信息的人类临床试验正在进行中。
相似文献
1
The pathophysiology of fragile X (and what it teaches us about synapses).
Annu Rev Neurosci. 2012;35:417-43. doi: 10.1146/annurev-neuro-060909-153138. Epub 2012 Apr 5.
2
The state of synapses in fragile X syndrome.
Neuroscientist. 2009 Oct;15(5):549-67. doi: 10.1177/1073858409333075. Epub 2009 Mar 26.
3
Altered synaptic plasticity in a mouse model of fragile X mental retardation.
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50. doi: 10.1073/pnas.122205699.
4
Metabotropic glutamate receptors and fragile x mental retardation protein: partners in translational regulation at the synapse.
Sci Signal. 2008 Feb 5;1(5):pe6. doi: 10.1126/stke.15pe6.
5
Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function.
Neuron. 2008 Oct 23;60(2):201-14. doi: 10.1016/j.neuron.2008.10.004.
6
Metabotropic glutamate receptor activation regulates fragile x mental retardation protein and FMR1 mRNA localization differentially in dendrites and at synapses.
J Neurosci. 2004 Mar 17;24(11):2648-55. doi: 10.1523/JNEUROSCI.0099-04.2004.
7
Dysregulation of mTOR signaling in fragile X syndrome.
J Neurosci. 2010 Jan 13;30(2):694-702. doi: 10.1523/JNEUROSCI.3696-09.2010.
8
Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of Fragile X Syndrome.
J Neurosci. 2019 Sep 18;39(38):7453-7464. doi: 10.1523/JNEUROSCI.1443-17.2019. Epub 2019 Jul 26.
9
Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice.
Hum Mol Genet. 2013 Mar 15;22(6):1180-92. doi: 10.1093/hmg/dds525. Epub 2012 Dec 18.
10
The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain.
Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2180-5. doi: 10.1073/pnas.0409803102. Epub 2005 Jan 31.
引用本文的文献
1
Autophagy controls the hippocampal postsynaptic organization and affects cognition in a mouse model of Fragile X syndrome.
Mol Psychiatry. 2025 Sep 10. doi: 10.1038/s41380-025-03207-6.
2
Autophagy controls the hippocampal postsynaptic organization and affects cognition in a mouse model of Fragile X syndrome.
Res Sq. 2025 Aug 27:rs.3.rs-4415392. doi: 10.21203/rs.3.rs-4415392/v1.
3
The relationship between immune cell infiltration and necroptosis gene expression in sepsis: an analysis using single-cell transcriptomic data.
Front Cell Infect Microbiol. 2025 Aug 11;15:1618438. doi: 10.3389/fcimb.2025.1618438. eCollection 2025.
4
From Discovery to Innovative Translational Approaches in 80 Years of Fragile X Syndrome Research.
Biomedicines. 2025 Mar 27;13(4):805. doi: 10.3390/biomedicines13040805.
5
Compensatory Regulation of Excitation/Inhibition Balance in the Ventral Hippocampus: Insights from Fragile X Syndrome.
Biology (Basel). 2025 Mar 31;14(4):363. doi: 10.3390/biology14040363.
6
Erasing "bad memories": reversing aberrant synaptic plasticity as therapy for neurological and psychiatric disorders.
Mol Psychiatry. 2025 Apr 10. doi: 10.1038/s41380-025-03013-0.
7
Impairment in the homeostatic recruitment of layer 5/6 neurons following whisker stimulation in Fmr1 KO mice.
Neurobiol Dis. 2025 Apr;207:106837. doi: 10.1016/j.nbd.2025.106837. Epub 2025 Feb 10.
8
Ascorbic Acid Ameliorates Molecular and Developmental Defects in Human-Induced Pluripotent Stem Cell and Cerebral Organoid Models of Fragile X Syndrome.
Int J Mol Sci. 2024 Nov 26;25(23):12718. doi: 10.3390/ijms252312718.
9
Deep functional measurements of Fragile X syndrome human neurons reveal multiparametric electrophysiological disease phenotype.
Commun Biol. 2024 Nov 6;7(1):1447. doi: 10.1038/s42003-024-07120-6.
10
Voltage-gated potassium channels as a potential therapeutic target for the treatment of neurological and psychiatric disorders.
Front Cell Neurosci. 2024 Oct 1;18:1449151. doi: 10.3389/fncel.2024.1449151. eCollection 2024.
本文引用的文献
1
Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities.
Cold Spring Harb Perspect Biol. 2012 Mar 1;4(3):a009886. doi: 10.1101/cshperspect.a009886.
2
The effect of an mGluR5 inhibitor on procedural memory and avoidance discrimination impairments in Fmr1 KO mice.
Genes Brain Behav. 2012 Apr;11(3):325-31. doi: 10.1111/j.1601-183X.2011.00763.x. Epub 2012 Jan 19.
3
BC1-FMRP interaction is modulated by 2'-O-methylation: RNA-binding activity of the tudor domain and translational regulation at synapses.
Nucleic Acids Res. 2012 May;40(9):4086-96. doi: 10.1093/nar/gkr1254. Epub 2012 Jan 11.
4
Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome.
Neurobiol Dis. 2012 Mar;45(3):1145-52. doi: 10.1016/j.nbd.2011.12.037. Epub 2011 Dec 29.
5
Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the ΔRG mouse model of tuberous sclerosis complex.
Neurobiol Dis. 2012 Mar;45(3):1101-10. doi: 10.1016/j.nbd.2011.12.028. Epub 2011 Dec 16.
6
Mutations causing syndromic autism define an axis of synaptic pathophysiology.
Nature. 2011 Nov 23;480(7375):63-8. doi: 10.1038/nature10658.
7
Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein.
Neuron. 2011 Nov 17;72(4):630-42. doi: 10.1016/j.neuron.2011.09.033.
8
Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders.
Pharmacol Rev. 2012 Jan;64(1):65-87. doi: 10.1124/pr.110.003053. Epub 2011 Nov 16.
9
Elevated levels of the vesicular monoamine transporter and a novel repetitive behavior in the Drosophila model of fragile X syndrome.
PLoS One. 2011;6(11):e27100. doi: 10.1371/journal.pone.0027100. Epub 2011 Nov 2.
10
In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation.
Hum Mol Genet. 2012 Feb 15;21(4):900-15. doi: 10.1093/hmg/ddr527. Epub 2011 Nov 11.
Zotero 插件