神经营养因子前体调节细胞凋亡

神经营养因子前体 (ｐｒｏｎｅｕｒｏｅｒｏｐｈｉｎｓ ,Ｐｒｏ ＮＴ)是成熟的神经营养因子的前体物质 ,过去认为它没有生物学活性。但目前ＲａｍｅｃＬｅｅ等研究发现Ｐｒｏ ＮＴ可调节细胞凋亡。借助ｗｅｓｔｅｒｎｂｌｏｔ等技术发现 ,ｐｒｏ ＮＴ在细胞外可被纤溶酶和基质金属蛋白酶 (ＭＭＰ 3、ＭＭＰ 7)水解。并且 ,该前体物质对培养的神经细胞的作用与成熟的神经营养因子不同。它与Ｐ75ＮＴＲ有较高的亲和力 ,通过该受体引起神经细胞凋亡 ,而成熟的神经营养因子主要与Ｎｒｋ受体结合 ,促进神经细胞的生长发育。以上研究为探索其它神…     

脑源性神经营养因子前体蛋白生物学效应研究进展

神经营养因子是一类分泌性多肽类生长因子,可促进中枢和外周神经元的生长、存活以及分化,但其前体分子却具有不同的生物学活性,也有着不同的受体以及细胞内信号通路。本文对近年来关于脑源性神经营养因子前体蛋白的研究予以综述,着重讨论其在神经损伤与情绪障碍和神经退行性变疾病模型中的作用。     

神经营养因子

神经营养因子(Neurotrophin)是一类含量极少,对神经系统生命活动非常重要的、可溶性多肽因子。它们来源于靶细胞,逆向营养神经元,对脊椎动物神经系统的发生、发育、成     

睫状神经营养因子研究进展

睫状神经营养因子（ＣＮＴＦ）能够促进多种神经元的存活,在神经系统发育、分化和损伤修复过程中具有重要作用。睫状神经营养因子与白血病抑制因子、白细胞介素６有相似的空间结构,它们的受体组成也相关。睫状神经营养因子的神经营养作用研究为临床治疗神经系统疾病带来了新的希望。     

神经营养因子

神经营养因子范明蒲小平（军事医学科学院基础医学研究所,北京１００８５０）近年来,在基础与临床研究中常遇到“神经营养因子”,“神经生长因子”,“神经营养素”等名词混用的情况,有必要加以澄清。这里,笔者仅提出几点看法,供国内同行讨论。神经生长因子（ｎｅｒ...     

胶质细胞源神经营养因子研究进展

叙述了新近纯化的胶质细胞源神经营养因子（ＧＤＮＦ）的生物功能及其在鼠胚胎的分布,着重介绍了该因子对损伤的多巴胺能神经元及运动神经元促进存活,修复损伤及再生的活性。     

神经营养因子

神经营养因子(neurotrophic factor)是多肽。这些因子在发育神经系统中支持神经元生长、分化和存活;在成年神经系统中有维持神经元的作用。最近的资料还支持一种新的观点,即有些神经营养因子可能与改善脑发育中神经元之间的联系有关。在神经营养因子中,一些因子主要作用于神经元;而另一些因子既作用于神经元,也作用于非神经元。     

睫状体神经营养因子

睫状体神经营养因子是一种多功能的细胞因子,它在体外和体内对中枢神经系和周围神经系的运动神经元、感觉神经元、交感神经元、副交感神经元的发育、存活、分化、损伤后修复等方面都起重要作用。本介绍了睫状体神经营养因子及其受体的结构和功能、它们的基因以及用基因工作生产的人睫状体神经营养因子及其临床应用前景。     

神经营养因子与神经干细胞

生长因子在神经干细胞的增殖,分化和存活过程中有重要作用。神经营养因子是其中的一类,它包括神经生长因子（NGF）家族,胶质源性神经营养因子（GDNF）家族和其它神经营养因子。NGF家族包括NGF,BDNF,NT－3,NT－4／5和NT－6。这一家族可促进epidermic growth facter(EGF)反应 海马及前脑室管膜下区神经干细胞的存活和分化。GDNF家族包括GDNF,NTN,PSP和ART。GDNF家族促神经发育的作用主要在外周,它促进肠神经嵴前体细胞的存活和增殖,且对外周感觉神经的发育至关重要。其它生长因子如bFGF和EGF,它们能促进神经干细胞增殖和存活;CNTF和LIF等在神经干细胞的分化中也有重要作用。     

神经营养因子

神经营养因子能够促进神经细胞的存活．生长和分化．神经营养因子可以通过逆向、正向、自分泌和非分泌等途径发挥神经营养作用．神经营养因子的作用具有多样性和复杂性,不同神经营养因子具有相互交叉但又各自特定的神经营养活性．种经营养因子研究为治疗早老性痴呆、帕金森病、肌萎缩侧索硬化症等神经系统退行性病变以及外周神经损伤带来了新希望。     

NRH2 is a trafficking switch to regulate sortilin localization and permit proneurotrophin‐induced cell death

Proneurotrophins mediate neuronal apoptosis using a dual receptor complex of sortilin and p75^NTR. Although p75^NTR is highly expressed on the plasma membrane and accessible to proneurotrophin ligands, sortilin is primarily localized to intracellular membranes, limiting the formation of a cell surface co‐receptor complex. Here, we show that the mammalian p75^NTR homologue NRH2 critically regulates the expression of sortilin on the neuronal cell surface and promotes p75^NTR and sortilin receptor complex formation, rendering cells responsive to proneurotrophins. This is accomplished by interactions between the cytoplasmic domains of NRH2 and sortilin that impair lysosomal degradation of sortilin. In proneurotrophin‐responsive neurons, acute silencing of endogenous NRH2 significantly reduces cell surface‐expressed sortilin and abolishes proneurotrophin‐induced neuronal death. Thus, these data suggest that NRH2 acts as a trafficking switch to impair lysosomal‐dependant sortilin degradation and to redistribute sortilin to the cell surface, rendering p75^NTR‐expressing cells susceptible to proneurotrophin‐induced death.     

p75NTR介导神经细胞凋亡研究进展

在神经发育过程中,神经营养因子通过其低亲和力受体p75NTR与高亲和力受体Trk的介导,在神经元的存活、分化与髓鞘形成中发挥着重要的作用;与存活、生长这些“正性”信号相反,p75NTR也介导受损后及新生神经元凋亡这一“负性”信号。一直以来,p75NTR是如何介导这些截然相反的功能仍不清楚,尤其是何时引起凋亡,其机制如何更是所知甚少。近来,随着s-p75NTR、proNGF、sortilin复合受体等的发现,其中的一些机制开始有所明朗。本文就p75NTR介导神经元凋亡的研究进展做一综述。     

Proteolytic processing of the p75 neurotrophin receptor: A prerequisite for signalling?

The common neurotrophin receptor (p75(NTR) ) regulates various functions in the developing and adult nervous system. Cell survival, cell death, axonal and growth cone retraction, and regulation of the cell cycle can be regulated by p75(NTR) -mediated signals following activation by either mature or pro-neurotrophins and in combination with various co-receptors, including Trk receptors and sortilin. Here, we review the known functions of p75(NTR) by cell type, receptor-ligand combination, and whether regulated intra-membrane proteolysis of p75(NTR) is required for signalling. We highlight that the generation of the intracellular domain fragment of p75(NTR) is associated with many of the receptor functions, regardless of its ligand and co-receptor interactions.     

Motoneuron programmed cell death in response to proBDNF

Motoneurons (MN) as well as most neuronal populations undergo a temporally and spatially specific period of programmed cell death (PCD). Several factors have been considered to regulate the survival of MNs during this period, including availability of muscle-derived trophic support and activity. The possibility that target-derived factors may also negatively regulate MN survival has been considered, but not pursued. Neurotrophin precursors, through their interaction with p75(NTR) and sortilin receptors have been shown to induce cell death during development and following injury in the CNS. In this study, we find that muscle cells produce and secrete proBDNF. ProBDNF through its interaction with p75(NTR) and sortilin, promotes a caspase-dependent death of MNs in culture. We also provide data to suggest that proBDNF regulates MN PCD during development in vivo.     

Human ProNGF: biological effects and binding profiles at TrkA, P75NTR and sortilin

Nerve growth factor (NGF) promotes cell survival via binding to the tyrosine kinase receptor A (TrkA). Its precursor, proNGF, binds to p75(NTR) and sortilin receptors to initiate apoptosis. Current disagreement exists over whether proNGF acts neurotrophically following binding to TrkA. As in Alzheimer's disease the levels of proNGF increase and TrkA decrease, it is important to clarify the properties of proNGF. Here, wild-type and cleavage-resistant mutated forms (M) of proNGF were engineered and their binding characteristics determined. M-proNGF and NGF bound to p75(NTR) with similar affinities, whilst M-proNGF had a lower affinity than NGF for TrkA. M-proNGF behaved neurotrophically, albeit less effectively than NGF. M-proNGF addition resulted in phosphorylation of TrkA and ERK1/2, and in PC12 cells elicited neurite outgrowth and supported cell survival. Conversely, M-proNGF addition to cultured cortical neurons initiated caspase 3 cleavage. Importantly, these biological effects were shown to be mediated by unprocessed M-proNGF. Surprisingly, binding of the pro region alone to TrkA, at a site other than that of NGF, caused TrkA and ERK1/2 phosphorylation. Our data show that M-proNGF stimulates TrkA to a lesser degree than NGF, suggesting that in Alzheimer brain the increased proNGF : NGF and p75(NTR) : TrkA ratios may permit apoptotic effects to predominate over neurotrophic effects.     

p75 neurotrophin receptor mediates apoptosis in transit-amplifying cells and its overexpression restores cell death in psoriatic keratinocytes

p75 neurotrophin receptor (p75NTR) belongs to the TNF-receptor superfamily and signals apoptosis in many cell settings. In human epidermis, p75NTR is mostly confined to the transit-amplifying (TA) sub-population of basal keratinocytes. Brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4), which signals through p75NTR, induces keratinocyte apoptosis, whereas β-amyloid, a ligand for p75NTR, triggers caspase-3 activation to a greater extent in p75NTR transfected cells. Moreover, p75NTR co-immunoprecipitates with NRAGE, induces the phosphorylation of c-Jun N-terminal kinase (JNK) and reduces nuclear factor kappa B (NF-κB) DNA-binding activity. p75NTR also mediates pro-NGF-induced keratinocyte apoptosis through its co-receptor sortilin. Furthermore, BDNF or β-amyloid cause cell death in TA, but not in keratinocyte stem cells (KSCs) or in p75NTR silenced TA cells. p75NTR is absent in lesional psoriatic skin and p75NTR levels are significantly lower in psoriatic than in normal TA keratinocytes. The rate of apoptosis in psoriatic TA cells is significantly lower than in normal TA cells. BDNF or β-amyloid fail to induce apoptosis in psoriatic TA cells, and p75NTR retroviral infection restores BDNF- or β-amyloid-induced apoptosis in psoriatic keratinocytes. These results demonstrate that p75NTR has a pro-apoptotic role in keratinocytes and is involved in the maintenance of epidermal homeostasis.     

RanBPM is a novel binding protein for p75NTR

The neurotrophin receptor p75NTR can induce signal transduction both in vivo and in vitro. The mechanisms by which p75NTR transduces signals have remained mostly unknown. Using yeast two-hybrid system, we identified the Ran-binding protein (RanBPM) as an interactor with the intracytoplasmic domain of p75NTR (p75ICD). The interaction was then validated by immunoprecipitation in mammalian cells and immunoblotting analysis. The domain in p75ICD interacting with RanBPM was mapped to the death domain.     

The p35/CDK5 signaling is regulated by p75NTR in neuronal apoptosis after intracerebral hemorrhage

The p75 neurotrophin receptor (p75NTR), a member of tumor necrosis factor receptor superfamily, involves in neuronal apoptosis after intracerebral hemorrhage (ICH). It has been previously demonstrated that phosphorylation of p35 is a crucial factor for fighting against the proapoptotic p25/CDK5 signaling in neuronal apoptosis. Then, in ICH models of rats and primary cortical neurons, we found that the expressions of p75NTR, p-histone H1 (the kinase activity of CDK5), p25, Fas-associated phosphatase-1 (FAP-1), and phosphorylated myocyte enhancer factor 2D (p-MEF2D) were enhanced after ICH, whereas the expression of p35-Thr(138) was attenuated. Coimmunoprecipitation analysis indicated several interactions as follows: p35/p25 and CKD5, p75NTR and p35, as well as p75NTR and FAP-1. After p75NTR or FAP-1 depletion with double-stranded RNA interference in PC12 cells, the levels of p25 and p-histone H1 were attenuated, whereas p35-Thr(138) was elevated. Considering p75NTR has no effect of dephosphorylation, our results suggested that p75NTR might promote the dephosphorylation of p35-Thr(138) via interaction with FAP-1, and the p75NTR/p35 complex upregulated p25/CDK5 signaling to facilitate the neuronal apoptosis following ICH. So, in the study, we aimed to provide a theoretical and experimental basis that p75NTR could be regulated to reduce neuronal apoptosis following ICH for potential clinical treatment.     

戊四氮点燃癫痫大鼠海马P75NTR及NF-κB的表达变化

目的探讨戊四氮点燃癫痫大鼠海马神经营养因子受体P75NTR及核转录因子NF-κB表达的变化,以探讨癫痫的发病机制。方法戊四氮腹腔注射诱导大鼠癫痫持续状态（SE）,观察大鼠行为学改变,分别选取1,6,24,72h四个时间点运用反转录多聚酶链反应（RT-PCR）方法检测SE大鼠和对照组海马P75NTR mRNA及NF-κB mRNA的表达。结果SE后6h,P75NTR和NF-κB表达开始增高,24h达高峰（P〈0.01）,72h略有下降,但仍高于对照组水平（P〈0.05）。各组间两两比较差异有统计学意义（P〈0.05）。结论癫痫SE时,P75NTR高表达同时伴NF-κB活性增强,二者变化具有相关性,可能为SE致痫的共同途径。     

Amyloid beta1–42 (Aβ42) up‐regulates the expression of sortilin via the p75NTR/RhoA signaling pathway

Sortilin, a Golgi sorting protein and a member of the VPS10P family, is the co‐receptor for proneurotrophins, regulates protein trafficking, targets proteins to lysosomes, and regulates low density lipoprotein metabolism. The aim of this study was to investigate the expression and regulation of sortilin in Alzheimer's disease (AD). A significantly increased level of sortilin was found in human AD brain and in the brains of 6‐month‐old swedish‐amyloid precursor protein/PS1dE9 transgenic mice. Aβ₄₂ enhanced the protein and mRNA expression levels of sortilin in a dose‐ and time‐dependent manner in SH‐SY5Y cells, but had no effect on sorLA. In addition, proBDNF also significantly increased the protein and mRNA expression of sortilin in these cells. The recombinant extracellular domain of p75^NTR (P75ECD‐FC), or the antibody against the extracellular domain of p75^NTR, blocked the up‐regulation of sortilin induced by Amyloid‐β protein (Aβ), suggesting that Aβ₄₂ increased the expression level of sortilin and mRNA in SH‐SY5Y via the p75^NTR receptor. Inhibition of ROCK, but not Jun N‐terminal kinase, suppressed constitutive and Aβ₄₂‐induced expression of sortilin. In conclusion, this study shows that sortilin expression is increased in the AD brain in human and mice and that Aβ₄₂ oligomer increases sortilin gene and protein expression through p75^NTR and RhoA signaling pathways, suggesting a potential physiological interaction of Aβ₄₂ and sortilin in Alzheimer's disease.