Roles of nerve growth factor and brain-derived neurotrophic factor and their precursors in nervous system

doi:10.3969/j.issn.2095-4344.0300

Abstract

Abstract:

BACKGROUND: More than 20 neurotrophic factors have been found. Among them, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are the most widely distributed growth factors in the central nervous system, and they are responsible for the growth, development and neuronal plasticity of the central nervous system and even of the entire brain.
OBJECTIVE: To fully understand NGF and BDNF, learn more about their role in the repair of nervous system damage, and to review the research progress in NGF and BDNF and their precursors.
METHODS: A computer-based online retrieval of PubMed and CNKI databases was performed to search relevant papers about neurotrophic factors, NGF and BDNF. The keywords were “nerve growth factor (NGF), proform of nerve growth factor (proNGF), brain-derived neurotrophic factor (BDNF), precursor for brain-derived neurotrophic factor (proBDNF), neurotrophic factor, neurotrophin receptor” in English and Chinese, respectively.
RESULTS AND CONCLUSION: NGF has the biological function of protecting neurons after peripheral nerve injury. The precursor of NGF simultaneously forms trimers of signal transducers with receptors p75NTR and Sortilin and induces apoptosis and death of nerves post-nerve injury. PDNF preferentially binds to TrkB to produce biological effects that promote synaptic growth or support the survival and differentiation of neurons. The precursor of BDNF preferentially binds p75NTR and Sortilin to trigger neuronal apoptosis. With the deepening of the research, it has been found that the precursors of NGF and BDNF exhibit the opposite biological effects on the mature NGF and BDNF, but the specific mechanism of action remains unclear.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Neurturin, Nerve Growth Factor, Peripheral Nerves, Tissue Engineering

CLC Number:

R318

Dai Yun-fei1, Wang Tong-tong1, Ma Wei1, Yang Jin-wei1, 2, Wang Xian-bin1, Zhang Tong2, Su Ping3, Guo Jian-hui2, Li Li-yan1. Roles of nerve growth factor and brain-derived neurotrophic factor and their precursors in nervous system[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(28): 4580-4586.

Figures/Tables 3

实验证实神经生长因子前体可以在中枢神经系统和外周神经系统等部位检测到，而神经生长因子作为成熟的蛋白在中枢神经系统和外周神经系统等部位检测到的量却很少，说明神经元和星形胶质细胞可以分泌神经生长因子前体，而不分泌成熟的神经生长因子[16]。研究发现神经生长因子前体在胞外的裂解主要是通过纤溶酶起作用[17]，主要依赖基质金属蛋白酶3和7[18]。因此推测，细胞内合成的神经生长因子前体可以发挥促神经元存活的生物学功能，也可以在胞外继续存在并产生促细胞凋亡的生物学作用。 2.3 脑源性神经营养因子及前体脑源性神经生长因子是由119个氨基酸组成的一类相对分子质量为12 000的分泌蛋白(表1)，其含有3对二硫键，可在体内以二聚体形式存在[19]。脑源性神经生长因子主要分布在中枢神经系统，在海马和大脑皮质组织中含量最高。脑源性神经生长因子的表达水平在发育阶段中受到调控，在出生 15 d时表达量最高，而后逐渐降低至成体水平[20]。脑区兴奋性刺激可以提高大脑中脑源性神经生长因子mRNA的表达水平[21]。神经元的兴奋可以诱导脑源性神经生长因子在突起处聚集后释放进入到突出间隙[22]。脑源性神经营养因子前体是成熟脑源性神经生长因子的前体形式，肽链长度为249个氨基酸，氨基酸序列第57和58位点是酶切的识别位点，相对分子质量为 32 000-36 000(表1)。早期研究认为脑源性神经生长因子的基因先转录翻译成脑源性神经营养因子前体，之后在高尔基体和内质网中被丝氨酸蛋白酶裂解，释放出具有生物活性的羧基端成为成熟的脑脑源性神经生长因子蛋白被分泌到胞外从而发挥生物学功能，脑源性神经营养因子前体作为中间物质不发挥生物学功能[23]。近来的研究认为脑源性神经营养因子前体不仅可以作为脑源性神经生长因子的前体形式存在，本身也可由神经元突触直接分泌到细胞外，发挥与脑源性神经生长因子不同的功能[24]。在细胞外，脑源性神经营养因子前体可以在纤维蛋白溶酶原活化物[25]、丝氨酸蛋白纤溶酶[26]、金属蛋白酶的作用下裂解为成熟的脑源性神经生长因子[27]。胞外未裂解的脑源性神经营养因子前体可以被星形胶质细胞摄取，并在适当的时候释放，使脑源性神经营养因子前体能够循环利用[28]。在细胞内，高尔基体内的内源性枯草杆菌蛋白酶可以将脑源性神经营养因子前体裂解成脑源性神经生长因子；在未成熟的分泌颗粒中可以通过蛋白前体转化酶的作用生成脑源性神经生长因子[29]。通过使用特异性的脑源性神经营养因子前体的前体结构域抗体研究发现，脑源性神经营养因子前体广泛存在于中枢神经系统包括脊髓背角、三叉神经核、孤束核、杏仁核、海马、下丘脑和大脑皮质等[30]。通过对大鼠的各年龄段研究发现老龄大鼠的海马中大量聚集脑源性神经营养因子前体[31]。除中枢神经系统外，大鼠外周组织的浅表神经末梢、人的唾液和成年海鲈的肝脏、肾脏以及肌肉上也有脑源性神经营养因子前体的分布[32]。 2.4 神经生长因子和脑源性神经生长因子的受体神经生长因子通过与细胞膜表面的受体结合而发挥作用，根据神经生长因子表面糖蛋白与细胞膜上凝集素结合能力的不同，其受体可被分为高亲和力受体Trk A和低亲和力受体p75NTR[33]。其中p75NTR由于能以相同的亲和力与所有的神经营养素结合，而被称为神经营养素受体[34]。这2种受体分别与神经生长因子相互作用，调控不同的信号通路，对神经元的存活、生长、分化和功能都有重要的调控作用[35]。当Trk A与p75NTR共表达时，p75NTR能够增加Trk A受体对神经生长因子的结合力，从而促进神经突起的生长和存活，也能提升其后的信号传导速度[36]；但是，如果神经生长因子仅与p75NTR结合，则会诱导细胞凋亡[37]。p75也能提高Trk A识别并增强与神经生长因子结合的特异性。如当成纤维细胞中p75和Trk A同时表达时，Trk A只能与神经生长因子结合从而自动磷酸化；而只表达Trk A时，神经生长因子、神经营养因子Ⅲ、神经营养因子Ⅳ、神经营养因子V均能导致Trk A的自动磷酸化[38]。脑源性神经生长因子的受体有p75NTR和TrkB，其前体的受体有p75NTR、TrkB和sortilin[39]。其中，p75NTR为脑源性神经生长因子的低亲和力受体[40]，TrkB为脑源性神经生长因子的高亲和力受体，脑源性神经生长因子通过与高亲和受体TrkB结合发挥促进中枢神经系统和外周神经系统的神经元与胶质细胞的分化和存活、髓鞘形成、神经元迁移和轴突伸缩，以及保护损伤后的神经元等生物学作用[41]。而sortilin是最近发现的vps10p-D (vacuolar protein sorting 10 domain)受体家族成员。 2.4.1 TrkA受体 TrkA受体含有790个氨基酸且相对分子质量为120 000-160 000(表2)，是由原癌基因Trk编码的酪氨酸蛋白激酶家族成员，有3个亚型，分别是TrkA、TrkB和TrkC。神经营养因子可分别与其特异结合，其中神经生长因子可优先结合TrkA，脑源性神经生长因子和神经营养因子Ⅳ优先结合TrkB，神经营养因子Ⅲ优先结合TrkC[42]。Trk A是神经生长因子的特异性高亲和力受体，也是其功能性受体，神经生长因子只有与Trk A结合才能发挥出大多数生物学功能。Trk A的分子组成可以分为3个部分：细胞外结构域、跨膜结构域和胞内区。细胞外结构域具有识别并结合神经生长因子的功能；跨膜区和近膜结构域则负责信号的转导和活化；胞内区是Trk A的催化部位，也是Trk A发挥作用的关键部位[43]。神经生长因子与Trk A受体结合主要是通过免疫球蛋白C2结构域，通过跨膜结构域的帮助，在胞内酪氨酸激酶的磷酸化作用下启动并介导下游信号转导通路[44]。"

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