Department of Internal Medicine, Medical College, Najran University, Najran, Kingdom of Saudi Arabia.
Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, P.O. Box 14132, Baghdad, Iraq.
Mol Neurobiol. 2024 May;61(5):2469-2480. doi: 10.1007/s12035-023-03727-8. Epub 2023 Oct 28.
Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease of the brain. PD is characterized by motor and non-motor symptoms. The p75 neurotrophin receptor (p75NTR) is a functional receptor for different growth factors including pro-brain derived neurotrophic factor (pro-BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Consequently, this review aimed to illustrate the detrimental and beneficial role of p75NTR in PD. Diverse studies showed that p75NTR and its downstream signaling are intricate in the pathogenesis of PD. Nevertheless, pro-apoptotic and pro-survival pathways mediated by p75NTR in PD were not fully clarified. Of note, p75NTR plays a critical role in the regulation of dopaminergic neuronal survival and apoptosis in the CNS. Particularly, p75NTR can induce selective apoptosis of dopaminergic neurons and progression of PD. In addition, p75NTR signaling inhibits the expression of transcription factors which are essential for the survival of dopaminergic neurons. Also, p75NTR expression is connected with the severity of dopaminergic neuronal injury. These verdicts implicate p75NTR signaling in the pathogenesis of PD, though the underlying mechanistic pathways remain not elucidated. Collectively, the p75NTR signaling pathway induces a double-sword effect either detrimental or beneficial depending on the ligands and status of PD neuropathology. Therefore, p75NTR signaling seems to be protective via phosphoinositide 3-kinase (PI3K)/AKT and Bcl-2 and harmful via activation of JNK, caspase 3, nuclear factor kappa B (NF-κB), and RhoA pathways.
帕金森病（PD）是一种慢性进行性的脑退行性疾病。PD 的特征是运动和非运动症状。p75 神经营养素受体（p75NTR）是多种生长因子的功能性受体，包括脑源性神经营养因子前体（pro-BDNF）、神经营养因子 3（NT-3）和神经营养因子 4（NT-4）。因此，本综述旨在阐明 p75NTR 在 PD 中的有害和有益作用。多项研究表明，p75NTR 及其下游信号在 PD 的发病机制中非常复杂。然而，p75NTR 介导的促凋亡和促存活途径在 PD 中尚未完全阐明。值得注意的是，p75NTR 在中枢神经系统中多巴胺能神经元的存活和凋亡的调节中起着关键作用。特别是，p75NTR 可以诱导多巴胺能神经元的选择性凋亡和 PD 的进展。此外，p75NTR 信号抑制转录因子的表达，这些转录因子对于多巴胺能神经元的存活至关重要。此外，p75NTR 的表达与多巴胺能神经元损伤的严重程度有关。这些结论表明 p75NTR 信号参与了 PD 的发病机制，尽管其潜在的机制途径仍未阐明。总的来说，p75NTR 信号通路根据配体和 PD 神经病理学的状态，产生双重效应，既有害又有益。因此，p75NTR 信号似乎通过磷酸肌醇 3-激酶（PI3K）/AKT 和 Bcl-2 发挥保护作用，而通过激活 JNK、caspase 3、核因子 kappa B（NF-κB）和 RhoA 途径发挥有害作用。
