CRTC1对癫痫自噬和GluA2表达的调控机制。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Molecular Neurobiology Pub Date : 2025-05-10 DOI:10.1007/s12035-025-04971-w

Xueying Wang, Liqian Zhou, Lin Yang, Shaoping Huang, Yuying Wang, Dan Li

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引用次数: 0

摘要

本研究的目的是阐明camp调控的转录共激活物1 （CRTC1）调控癫痫患者自噬和GluA2表达的分子机制。方法：初步建立无镁癫痫细胞模型，采用全细胞膜片钳技术记录细胞放电情况。接下来，我们通过实验激活自噬，并利用RNA干扰技术确定了有效的CRTC1基因沉默方法。此外，我们建立了癫痫持续状态动物模型，并利用免疫荧光和Western Blot来阐明CRTC1在癫痫中调节自噬相关基因和GluA2表达的作用。结果：在无镁细胞外条件下观察小鼠海马神经元。自噬激活剂治疗可降低GluA2的表达；然而，CRTC1并没有被去磷酸化。CRTC1 siRNA抑制LC3和PSD95的表达，而CRTC1 siRNA干预恢复了GluA2的表达。结论：在癫痫病理过程中，CRTC1通过直接调节自噬间接影响突触相关蛋白和GluA2的表达。这项研究的发现揭示了治疗癫痫的新分子靶点。

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Regulatory Mechanism of CRTC1 on Autophagy and GluA2 Expression in Epilepsy.

The objective of this study was to elucidate the molecular mechanisms by which cAMP-regulated transcription coactivator1 (CRTC1) regulates autophagy and GluA2 expression in patients with epilepsy.

Methods: We initially established a magnesium-free epilepsy cell model and recorded cellular discharges using the whole-cell patch clamp technique. Next, we experimentally activated autophagy and identified effective methods for silencing the CRTC1 gene using RNA interference technology. Furthermore, we developed an animal models of status epilepticus and employed immunofluorescence and Western Blot to elucidate CRTC1's role in regulating autophagy-related genes and GluA2 expression in epilepsy.

Results: We observed mouse hippocampal neurons under magnesium-free extracellular conditions. Treatment with an autophagy activator decreased GluA2 expression; however, CRTC1 was not dephosphorylated. CRTC1 siRNA suppressed LC3 and PSD95 expression, whereas CRTC1 siRNA intervention restored GluA2 expression.

Conclusion: CRTC1 indirectly influences the expression of synaptic-related proteins and GluA2 by directly modulating autophagy during the pathological process of epilepsy. The findings of this study reveal novel molecular targets for the treatment of epilepsy.

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来源期刊

Molecular Neurobiology 医学-神经科学

CiteScore

9.00

自引率

2.00%

发文量

480

审稿时长

1 months

期刊介绍： Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.