Porcari Cristina, Cattaneo Stefano, Crippa Lucia, Simonato Michele, Bettegazzi Barbara
Department of Neuroscience and Rehabilitation, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.
Front Physiol. 2025 Jun 26;16:1618330. doi: 10.3389/fphys.2025.1618330. eCollection 2025.
Glial cell line-derived neurotrophic factor (GDNF) is a potent trophic factor essential for neuronal survival and function. Encoded by the GDNF gene, its mature protein arises from specific post-translational modifications and is secreted through distinct isoform-dependent pathways. Once released, GDNF binds to its receptors, GFRα1 and RET, activating downstream signaling cascades that regulate cell growth, differentiation, and survival. In the central nervous system, GDNF exerts protective effects on dopaminergic neurons-highlighted in Parkinson's disease research-and shows promise for modulating schizophrenia, depression, and addiction. Beyond dopaminergic pathways, GDNF influences synaptic plasticity in hippocampal neurons and supports GABAergic function. Glial cells also produce and respond to GDNF: astrocyte-derived GDNF can promote neuroprotection but also modulate microglial state and neuroinflammation. Other cell sources, such as pericytes and endothelial cells, contribute to GDNF levels, impacting blood-brain and blood-nerve barrier permeability. Peripherally, GDNF is critical for sympathetic and parasympathetic neuron development, somatic sensory neuron maintenance, and motor neuron reinnervation at the neuromuscular junction. Finally, GDNF has been recently implicated in tumour biology, underscoring its multifaceted role at the interface between beneficial and detrimental effects. Clinically, its therapeutic potential is being explored in different diseases, including neurodegenerative disorders and epilepsy. In this review, we will explore various aspects of GDNF biology and then focus our attention to the physiological mechanisms of GDNF-regulated processes in the central and peripheral nervous system, concluding with a brief perspective related to its therapeutic potential for central nervous system disorders. A deeper knowledge of the mechanisms regulating GDNF secretion and signaling, particularly the cellular source and the specificity of the GDNF-engaged intracellular signaling pathways, could be helpful to develop more precise therapeutic strategies for different CNS diseases.
胶质细胞系源性神经营养因子（GDNF）是一种对神经元存活和功能至关重要的强效营养因子。由GDNF基因编码，其成熟蛋白通过特定的翻译后修饰产生，并通过不同的异构体依赖性途径分泌。一旦释放，GDNF与其受体GFRα1和RET结合，激活下游信号级联反应，调节细胞生长、分化和存活。在中枢神经系统中，GDNF对多巴胺能神经元具有保护作用——这在帕金森病研究中得到了突出体现——并且在调节精神分裂症、抑郁症和成瘾方面显示出前景。除了多巴胺能途径，GDNF还影响海马神经元的突触可塑性并支持γ-氨基丁酸能功能。胶质细胞也产生并对GDNF作出反应：星形胶质细胞衍生的GDNF可以促进神经保护，但也能调节小胶质细胞状态和神经炎症。其他细胞来源，如周细胞和内皮细胞，也会影响GDNF水平，进而影响血脑屏障和血神经屏障的通透性。在周围神经系统中，GDNF对交感和副交感神经元发育、躯体感觉神经元维持以及神经肌肉接头处的运动神经元再支配至关重要。最后，GDNF最近被认为与肿瘤生物学有关，这突出了其在有益和有害作用之间界面的多方面作用。临床上，正在不同疾病中探索其治疗潜力，包括神经退行性疾病和癫痫。在这篇综述中，我们将探讨GDNF生物学的各个方面，然后将注意力集中在GDNF调节中枢和周围神经系统过程的生理机制上，最后简要展望其对中枢神经系统疾病的治疗潜力。深入了解调节GDNF分泌和信号传导的机制，特别是GDNF参与的细胞来源和细胞内信号通路的特异性，可能有助于为不同的中枢神经系统疾病制定更精确的治疗策略。
