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浙江大学学报(医学版)  2020, Vol. 49 Issue (4): 500-507    DOI: 10.3785/j.issn.1008-9292.2020.08.15
综述     
模式生物神经轴突再生的研究进展
蒋沛然(),王志萍*()
浙江大学医学院脑科学与脑医学系, 浙江 杭州 310058
Progress on axon regeneration in model organisms
JIANG Peiran(),WANG Zhiping*()
School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China
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摘要:

与外周神经系统的神经元不同,中枢神经系统中成熟的神经元往往无法实现损伤后再生。近期,有研究发现钙离子传导损伤信号、线粒体运输、细胞骨架重构和蛋白质合成在轴突再生中发挥重要的功能。神经元损伤发生后,细胞内钙离子浓度升高,通过钙离子介导的环腺苷酸(cAMP)-蛋白激酶A(PKA)信号通路活化可激活下游双亮氨酸激酶(DLK),在多种动物损伤模型中促进轴突再生。轴突再生需要生长锥的重构,这一进程需要细胞骨架的有序组装,在损伤处表达特定促进微管和微丝聚合的基因可有效促进生长锥的重构。此外,负责供能的线粒体也会影响生长锥的重构和轴突再生能力。最后,研究还发现多个调控基因表达与蛋白合成的通路可促进轴突再生。本综述将重点概括这些对轴突再生有重要作用的生理过程和分子机制。

关键词: 轴突再生线粒体运输模式生物综述    
Abstract:

Different from neurons in the peripheral nervous system, mature neurons in the mammalian central nervous system often fail to regenerate after injury. Recent studies have found that calcium transduction, injury signaling, mitochondrial transportation, cytoskeletal remodeling and protein synthesis play essential roles in axon regeneration. Firstly, axon injury increases the intracellular concentration of calcium, and initiates the injury signaling pathways including cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and dual leucine kinase (DLK), which are found to promote axon regeneration in multiple animal injury models. The second step for axonal regrowth is to rebuild growth cones. Overexpressing proteins that promote dynamics of microtubules and actin filaments is beneficial for the reassembly of cytoskeletons and initiation of new growth cones. Thirdly, mitochondria, the power factory for cells, also play important roles in growth cone formation and axonal extension. The last but not the least important step is the regulation of gene transcription and protein translation to sustain the regrowth of axons. This review summarizes important findings revealing the functions and mechanisms of these biological progresses.

Key words: Axon    Regeneration    Mitochondrial transportation    Model organisms    Review
收稿日期: 2020-05-20 出版日期: 2020-09-27
:  R338  
通讯作者: 王志萍     E-mail: peiranjiang@zju.edu.cn;z4wang@zju.edu.cn
作者简介: 蒋沛然(1995-), 女, 硕士研究生, 主要从事脊髓损伤和轴突再生研究; E-mail:peiranjiang@zju.edu.cn; https://orcid.org/0000-0002-6169-446X
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引用本文:

蒋沛然,王志萍. 模式生物神经轴突再生的研究进展[J]. 浙江大学学报(医学版), 2020, 49(4): 500-507.

JIANG Peiran,WANG Zhiping. Progress on axon regeneration in model organisms. J Zhejiang Univ (Med Sci), 2020, 49(4): 500-507.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.08.15        http://www.zjujournals.com/med/CN/Y2020/V49/I4/500

图 1  神经元轴突损伤后轴突再生调控模式图
与生理进程相关的基因和分子 对轴突再生的影响 作用机制 参考文献序号
MAPKKK:促分裂原活化的蛋白激酶激酶激酶;MAPKK:促分裂原活化的蛋白激酶激酶;MAPK:丝裂原激活蛋白激酶;CSPG:硫酸软骨素蛋白多糖;Nogo:勿动蛋白;GAP-43:生长相关蛋白43;CAP-23:皮质细胞骨架相关蛋白23;HDAC5:组蛋白去乙酰基酶5;cofilin1:肌动蛋白解聚因子;Tat-beclin1:一种诱导自噬的重组多肽;Fidgetin:一种微管切割蛋白;ARMCX1:哺乳动物特有的一种线粒体蛋白;Miro1:线粒体的Rho GTP酶1;mTOR:哺乳动物雷帕霉素靶蛋白;c-myc:核内癌基因;p53:人体抑癌基因;SOCS3:细胞因子信号抑制物3;PTEN:磷酸酶和张力蛋白同源物.
损伤信号感知
    环腺苷酸 促进 背根神经节分支发生损伤时,内源性环腺苷酸大量生成,通过蛋白激酶A激活轴突损伤后再生 6
  双亮氨酸激酶1 促进 MAPKKK家族成员,通过调控MAPKK的活性,稳定MAPK激活相关基因增强子结合蛋白1 mRNA,从而调控突触形成和轴突形态 7
  CSPG 抑制 细胞外抑制性因子,由损伤部位的星形胶质细胞分泌,抑制轴突再生 23
  Nogo 抑制 细胞外抑制性因子,由损伤部位的髓鞘碎片分泌,抑制轴突再生 24
细胞骨架重构
  GAP-43 & CAP-23 促进 生长锥蛋白,促进体外背根神经节的延伸 31
  HDAC5 促进 过表达HDAC5后,促进背根神经节损伤后轴突再生 30
  cofilin1 促进 仅过表达该基因即可实现显著的脊髓损伤后轴突再生 33
  Tat-beclin1 促进 通过降解微管解聚蛋白SCG10来提高微管的稳定性从而促进轴突再生 27
  Fidgetin 抑制 背根神经节中条件性敲降该蛋白表达,可实现损伤后神经突起损伤区域与脊髓的再连接 28
线粒体运输
  ARMCX1 促进 ARMCX1通过与Miro1互作,影响后者与Trak1/2驱动蛋白复合体的连接,调节视网膜神经节细胞线粒体的运输 32
  重组人生长蛋白 抑制 编码Syntaphilin,敲除重组人生长蛋白可使背根神经节轴突重获生长能力 37
基因表达与蛋白合成
  mTOR 促进 通过下游S6K1促进蛋白生成和轴突再生 39
  c-Myc 促进 核内癌基因,是禽类骨髓细胞瘤病毒转化序列的细胞同源物,可促进视网膜神经节细胞损伤模型的轴突再生 46
  p53 促进 抑癌基因,在细胞增殖、分化等过程中起重要转录调控作用,可促进感觉神经元的轴突再生 36
  SOCS3 抑制 轴突损伤时由炎症因子介导该基因表达上调,维持炎性反应,敲除该基因可促进轴突再生 44
  PTEN 抑制 磷酸酶和肌腱蛋白同源物,负向调控mTOR信号通路,在视网膜神经节细胞损伤后抑制轴突再生 45
表 1  参与调控轴突再生的部分重要基因和分子
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