Synergistic pathways in Parkinson's disease: The promise of FGF21 and ACE2

IF 12.4 1区 医学 Q1 CELL BIOLOGY
Tingting Liu , Jingwen Li , Zhengjia Yang , Jianshe Wei
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引用次数: 0

Abstract

Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder globally, is pathologically characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Current therapeutic strategies primarily alleviate clinical symptoms but lack efficacy in halting or reversing neurodegeneration. Recent studies have highlighted the FGF21-ACE2 signaling axis—a synergistic interaction between fibroblast growth factor 21 (FGF21) and angiotensin-converting enzyme 2 (ACE2)—as an emerging therapeutic target in PD due to its tripartite roles in neuroprotection, anti-inflammatory modulation, and metabolic homeostasis. Mechanistically, FGF21 activates neuroprotective pathways including phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and the extracellular signal-regulated kinase (ERK)1/2, suppressing apoptotic cascades, amplifying antioxidant defenses, and stimulating dopaminergic neuron differentiation. Conversely, ACE2 counterbalances neurotoxicity by converting angiotensin II (Ang II) to angiotensin-(1-7) [Ang-(1-7)], thereby mitigating neuroinflammation and oxidative stress. Their coordinated activity potently inhibits M1 microglial activation, downregulates pro-inflammatory cytokines (e.g., TNF-α), and bolsters astrocytic antioxidant responses while preserving metabolic equilibrium. Notably, this axis ameliorates mitochondrial dysfunction and attenuates α-synuclein (α-syn) aggregationvia modulation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling networks, collectively decelerating PD pathogenesis. Therapeutic interventions such as small-molecule agonists (e.g., diminazene aceturate, DIZE) and CRISPR-Cas9-mediated gene editing show potential to upregulate FGF21-ACE2 activity, while non-pharmacological approaches including exercise and ketogenic diets may synergistically enhance pathway efficacy. However, translational hurdles persist, including limited blood-brain barrier (BBB) permeability of therapeutics, off-target effects, and insufficient clinical validation. Future directions should prioritize deciphering dynamic molecular crosstalk within this pathway, engineering BBB-penetrant nanocarriers for targeted delivery, and conducting large-scale randomized controlled trials. This review underscores the FGF21-ACE2 axis as a multi-mechanistic therapeutic paradigm for PD, with its capacity for simultaneous modulation of neurodegeneration, inflammation, and metabolism positioning it as a superior candidate to conventional single-target therapies in achieving disease modification.
帕金森病的协同通路:FGF21和ACE2的前景
帕金森病(PD)是全球第二大最常见的神经退行性疾病,其病理特征是黑质(SN)多巴胺能神经元的进行性变性。目前的治疗策略主要是缓解临床症状,但在阻止或逆转神经变性方面缺乏疗效。最近的研究强调了FGF21-ACE2信号轴-成纤维细胞生长因子21 (FGF21)和血管紧张素转换酶2 (ACE2)之间的协同相互作用-由于其在神经保护,抗炎调节和代谢稳态中的三方面作用,作为PD的新兴治疗靶点。在机制上,FGF21激活包括磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B (AKT)和细胞外信号调节激酶(ERK)1/2在内的神经保护通路,抑制凋亡级联反应,增强抗氧化防御,刺激多巴胺能神经元分化。相反,ACE2通过将血管紧张素II (Ang II)转化为血管紧张素-(1-7)[Ang-(1-7)]来平衡神经毒性,从而减轻神经炎症和氧化应激。它们的协同活性有效地抑制M1小胶质细胞的激活,下调促炎细胞因子(如TNF-α),并在保持代谢平衡的同时增强星形胶质细胞的抗氧化反应。值得注意的是,该轴通过调节丝裂原活化蛋白激酶(MAPK)和核因子κB (NF-κB)信号网络,改善线粒体功能障碍并减弱α-突触核蛋白(α-syn)聚集,共同减缓PD的发病机制。治疗性干预,如小分子激动剂(如醋酸迪纳苯、DIZE)和crispr - cas9介导的基因编辑,显示出上调FGF21-ACE2活性的潜力,而非药物方法,包括运动和生酮饮食,可能协同增强途径的功效。然而,转化障碍仍然存在,包括治疗药物的血脑屏障(BBB)渗透性有限、脱靶效应和临床验证不足。未来的方向应该优先考虑破译这一途径中的动态分子串扰,设计靶向递送的bbb渗透纳米载体,并进行大规模随机对照试验。本综述强调FGF21-ACE2轴作为PD的多机制治疗范例,具有同时调节神经变性、炎症和代谢的能力,使其成为实现疾病改变的传统单靶点治疗的优越候选。
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来源期刊
Ageing Research Reviews
Ageing Research Reviews 医学-老年医学
CiteScore
19.80
自引率
2.30%
发文量
216
审稿时长
55 days
期刊介绍: With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.
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