中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2018, Vol. 13 ›› Issue (6): 1066-1080.doi: 10.4103/1673-5374.233451

• 原著:退行性病与再生 • 上一篇    下一篇

β淀粉样蛋白依赖性CRMP-2磷酸化可解离阿尔茨海默病的驱动蛋白：最新机制

  

  • 收稿日期:2018-03-30 出版日期:2018-06-15 发布日期:2018-06-15
  • 基金资助:

    这项研究得到了阿卜杜勒 - 阿齐兹国王大学研究生奖学金的支持; 国家多发性硬化症协会（美国）项目资助ID＃RG43981 / 1

Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer’s disease

Sara H. Mokhtar1, Min Joung Kim1, Kylie A. Magee1, Pei Mun Aui1, Speros Thomas1, Maha M. Bakhuraysah1, Amani A. Alrehaili1, Jae Young Lee1, David L. Steer2, Rachel Kenny3, Catriona McLean4, Michael F. Azari3, 5, Antonis Birpanagos6, Ewlina Lipiec7, Philip Heraud8, Bayden Wood8, Steven Petratos1   

  1. 1 Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria, Australia
    2 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
    3 Department of Anatomy & Developmental Biology, Monash University, Clayton, Victoria, Australia
    4 Department of Anatomical Pathology, Alfred Hospital, Prahran, Victoria, Australia
    5 School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
    6 Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Ilisia, Athens, Greece
    7 The Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, Department of Applied Spectroscopy, Radzikowskiego,Krakow, Poland
    8 Centre for Biospectroscopy and Department of Microbiology, Monash University, Clayton, Victoria, Australia
  • Received:2018-03-30 Online:2018-06-15 Published:2018-06-15
  • Contact: Steven Petratos,steven.petratos@monash.edu
  • Supported by:

    This study was supported by King Abdul-Aziz University postgraduate scholarship (to SHM); the National Multiple Sclerosis Society (USA) Project Grant ID #RG43981/1 (to SP).

PDF

287

摘要：

阿尔茨海默病（AD）在其淀粉样斑块和神经原纤维缠结的积聚这些特征性病理标志形成之前，顺行性轴突运输功能已受损。然而，启动这些细胞内损伤的关键蛋白仍未可知。Collapsin应答介体蛋白-2（CRMP-2）在驱动蛋白1依赖性轴突运输中起着不可或缺的作用，并且有证据表明CRMP-2磷酸化可释放驱动蛋白1。实验试图验证β淀粉样蛋白（Aβ）依赖性CRMP-2磷酸化破坏其与驱动蛋白-1（一种顺行的轴突运动蛋白）在AD中有关联的假设。发现来自AD患者的脑切片和裂解物在T555位点表现出CRMP-2磷酸化程度升高。在家族性AD（FAD）的转基因Tg2576小鼠模型中，随着年龄的增长，其在脑中表现出Aβ累积，pT555CRMP-2和营养不良性神经突的大量共定位。在SH-SY5Y分化的神经元培养物中，在T555位点的Aβ依赖性CRMP-2磷酸化程度也升高，并且这降低了CRMP-2与驱动蛋白-1的关联。而在神经元中不可磷酸化的CRMP-2形式过度表达促进了CRMP-2-驱动蛋白关联的重建和轴突延长。这些数据表明，在T555位点的Aβ-依赖性CRMP-2磷酸化可能直接损害顺行轴突转运蛋白功能，导致神经元功能障碍。

orcid:0000-0003-1211-4577(Steven Petratos)

关键词: 淀粉样&beta, 蛋白, 激酶, collapsin应答介体蛋白, 微管, 驱动蛋白, 微管蛋白

Abstract:

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles. Prior to the development of these characteristic pathological hallmarks of AD, anterograde axonal transport is impaired. However, the key proteins that initiate these intracellular impairments remain elusive. The collapsin response mediator protein-2 (CRMP-2) plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2 releases kinesin-1. Here, we tested the hypothesis that amyloid-beta (Aβ)-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1 (an anterograde axonal motor transport protein) in AD. We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site. Additionally, in the transgenic Tg2576 mouse model of familial AD (FAD) that exhibits Aβ accumulation in the brain with age, we found substantial co-localization of pT555CRMP-2 and dystrophic neurites. In SH-SY5Y differentiated neuronal cultures, Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1. The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation. These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function, leading to neuronal defects.

Key words: amyloid-beta protein, kinases, collapsin response mediator protein, microtubules, kinesin, tubulin