Ioannou Maria S, Fahnestock Margaret
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Int J Mol Sci. 2017 Mar 9;18(3):599. doi: 10.3390/ijms18030599.
Nerve growth factor (NGF) promotes the survival and differentiation of neurons. NGF is initially synthesized as a precursor, proNGF, which is the predominant form in the central nervous system. NGF and proNGF bind to TrkA/p75NTR to mediate cell survival and to sortilin/p75NTR to promote apoptosis. The ratio of TrkA to p75NTR affects whether proNGF and mature NGF signal cell survival or apoptosis. The purpose of this study was to determine whether the loss of TrkA influences p75NTR or sortilin expression levels, and to establish whether proNGF and mature NGF have a similar ability to switch between cell survival and cell death. We systematically altered TrkA receptor levels by priming cells with NGF, using small interfering RNA, and using the mutagenized PC12nnr5 cell line. We found that both NGF and proNGF can support cell survival in cells expressing TrkA, even in the presence of p75NTR and sortilin. However, when TrkA is reduced, proNGF signals cell death, while NGF exhibits no activity. In the absence of TrkA, proNGF-induced cell death occurs, even when p75NTR and sortilin levels are reduced. These results show that proNGF can switch between neurotrophic and apoptotic activity in response to changes in TrkA receptor levels, whereas mature NGF cannot. These results also support the model that proNGF is neurotrophic under normal circumstances, but that a loss in TrkA in the presence of p75NTR and sortilin, as occurs in neurodegenerative disease or injury, shifts proNGF, but not NGF, signalling from cell survival to cell death.
神经生长因子（NGF）可促进神经元的存活和分化。NGF最初作为前体proNGF合成，它是中枢神经系统中的主要形式。NGF和proNGF与TrkA/p75NTR结合以介导细胞存活，并与sortilin/p75NTR结合以促进细胞凋亡。TrkA与p75NTR的比例影响proNGF和成熟NGF是发出细胞存活信号还是凋亡信号。本研究的目的是确定TrkA的缺失是否会影响p75NTR或sortilin的表达水平，并确定proNGF和成熟NGF在细胞存活和细胞死亡之间切换的能力是否相似。我们通过用NGF预处理细胞、使用小干扰RNA以及使用诱变的PC12nnr5细胞系来系统性地改变TrkA受体水平。我们发现，即使存在p75NTR和sortilin，NGF和proNGF都可以支持表达TrkA的细胞的存活。然而，当TrkA减少时，proNGF发出细胞死亡信号，而NGF则无活性。在没有TrkA的情况下，即使p75NTR和sortilin水平降低，proNGF诱导的细胞死亡仍会发生。这些结果表明，proNGF可根据TrkA受体水平的变化在神经营养活性和凋亡活性之间切换，而成熟NGF则不能。这些结果还支持以下模型：在正常情况下，proNGF具有神经营养作用，但在神经退行性疾病或损伤中出现的p75NTR和sortilin存在时TrkA缺失的情况下，proNGF而非NGF的信号传导会从细胞存活转变为细胞死亡。
