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cdk5/p25 在 N2a 细胞中的表达增加导致神经丝蛋白的过度磷酸化和轴突运输受损。

Increased expression of cdk5/p25 in N2a cells leads to hyperphosphorylation and impaired axonal transport of neurofilament proteins.

机构信息

Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

出版信息

Life Sci. 2010 Mar 27;86(13-14):532-7. doi: 10.1016/j.lfs.2010.02.009. Epub 2010 Feb 12.

Abstract

AIMS

Alzheimer's disease (AD) is the leading cause of dementia. The increased cdk5 expression and enhanced phosphorylation of tau and NFs have been seen in AD patients. Our study aimed at investigating the effects of increased cdk5 activity on axonal transport of neurofilaments (NFs).

MAIN METHODS

In this study, we used a molecular engineering approach to overexpress cdk5/p25 in neuroblastoma N2a cells and investigated the effects on axonal transport with live cell imaging techniques.

KEY FINDINGS

In stably transfected cells, there was a 2.5-fold increase in cdk5 activity compared to non-transfected cells, which in turn led to a dramatic increase in phosphorylation of NFs and tau at several phosphorylation sites. Using time-lapse imaging technology, the transport of NFs was captured in the cells overexpressing cdk5/p25, which were also transiently transfected with fluorescence protein linked to the N-terminus of NF-M (EGFP-NFM). The cdk5/p25 cells displayed significantly slower rates of axonal transport of NFs, with accumulation of immobile NF clusters observed in the cell body. Roscovitine, an inhibitor of cdk5, significantly reversed this defect in axonal transport.

SIGNIFICANCE

These results suggest that increased cdk5 activity found in AD subjects may be crucially related to the pathogenesis of AD via an underlying mechanism by which it promotes accumulation of excessively phosphorylated cytoskeletal NF proteins, leading to the enduring impairment of axonal transport of NFs.

摘要

目的

阿尔茨海默病(AD)是痴呆的主要原因。在 AD 患者中,已经观察到 CDK5 表达增加,tau 和 NF 的磷酸化增强。我们的研究旨在研究 CDK5 活性增加对神经丝(NFs)轴突运输的影响。

主要方法

在这项研究中,我们使用分子工程方法在神经母细胞瘤 N2a 细胞中过表达 CDK5/p25,并使用活细胞成像技术研究其对轴突运输的影响。

主要发现

在稳定转染的细胞中,CDK5 活性比未转染的细胞增加了 2.5 倍,这反过来又导致 NF 和 tau 在几个磷酸化位点的磷酸化显著增加。使用延时成像技术,在过表达 CDK5/p25 的细胞中捕获 NF 的运输,这些细胞也瞬时转染了与 NF-M (EGFP-NFM)N 端连接的荧光蛋白。CDK5/p25 细胞显示出 NF 轴突运输的速度明显减慢,在细胞体中观察到不动的 NF 簇的积累。Roscovitine 是 CDK5 的抑制剂,可显著逆转 NF 轴突运输的这种缺陷。

意义

这些结果表明,AD 患者中发现的 CDK5 活性增加可能通过促进过度磷酸化细胞骨架 NF 蛋白积累的潜在机制与 AD 的发病机制密切相关,导致 NF 的轴突运输持久受损。

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