Mitrovic Marina, Selakovic Dragica, Jovicic Nemanja, Ljujic Biljana, Rosic Gvozden
Department of Medical Biochemistry, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
Int J Mol Sci. 2025 May 21;26(10):4926. doi: 10.3390/ijms26104926.
The neurotrophic system includes neurotrophins, such as brain-derived neurotrophic factor (BDNF) and its precursor proBDNF, which play conflicting roles in neuronal survival and apoptosis, with their balance having a significant impact on neurodegenerative outcomes. While BDNF is widely acknowledged as a potent neurotrophin that promotes neuronal survival and differentiation, its precursor, proBDNF, has the opposite effect, promoting apoptosis and neuronal death. This review highlights the new and unique aspects of BDNF/proBDNF interaction in the modulation of neuronal apoptotic pathways in neurodegenerative disorders. It systematically discusses the cross-talk in apoptotic signaling at the molecular level, whereby BDNF activates survival pathways such as PI3K/Akt and MAPK/ERK, whereas proBDNF activates p75NTR and sortilin to induce neuronal apoptosis via JNK, RhoA, NFkB, and Rac-GTPase pathways such as caspase activation and mitochondrial injury. Moreover, this review emphasizes the factors that affect the balance between proBDNF and BDNF levels within the context of neurodegeneration, including proteolytic processing, the expression of TrkB and p75NTR receptors, and extrinsic gene transcription regulators. Cellular injury, stress, or signaling pathway alterations can disrupt the balance of BDNF/proBDNF, which may be involved in apoptotic-related neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases. This review provides a comprehensive framework for targeting neurotrophin signaling in the development of innovative therapies for neuronal survival and managing apoptotic-related neurodegenerative disorders, addressing the mechanistic complexity and clinical feasibility of BDNF/proBDNF interaction.
神经营养系统包括神经营养因子，如脑源性神经营养因子（BDNF）及其前体proBDNF，它们在神经元存活和凋亡中发挥着相互矛盾的作用，二者的平衡对神经退行性病变的结果有重大影响。虽然BDNF被广泛认为是一种促进神经元存活和分化的强效神经营养因子，但其前体proBDNF却具有相反的作用，促进细胞凋亡和神经元死亡。本综述重点介绍了BDNF/proBDNF相互作用在神经退行性疾病中调节神经元凋亡途径方面的新的独特之处。它系统地讨论了分子水平上凋亡信号的相互作用，其中BDNF激活PI3K/Akt和MAPK/ERK等存活途径，而proBDNF激活p75NTR和sortilin，通过JNK、RhoA、NFkB以及Rac-GTPase途径（如半胱天冬酶激活和线粒体损伤）诱导神经元凋亡。此外，本综述强调了在神经退行性变背景下影响proBDNF和BDNF水平平衡的因素，包括蛋白水解加工、TrkB和p75NTR受体的表达以及外在基因转录调节因子。细胞损伤、应激或信号通路改变可破坏BDNF/proBDNF的平衡，这可能与阿尔茨海默病、帕金森病和亨廷顿病等与凋亡相关的神经退行性疾病有关。本综述为在开发神经元存活创新疗法和管理与凋亡相关的神经退行性疾病中靶向神经营养因子信号提供了一个全面的框架，阐述了BDNF/proBDNF相互作用的机制复杂性和临床可行性。
