Molecular mechanisms of GDNF/GFRA1/RET and PI3K/AKT/ERK signaling interplay in neuroprotection: Therapeutic strategies for treating neurological disorders

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides Pub Date : 2025-03-12 DOI:10.1016/j.npep.2025.102516

MD Nasiruddin Khan , Divya Choudhary , Sidharth Mehan , Zuber Khan , Ghanshyam Das Gupta , Acharan S. Narula

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引用次数: 0

Abstract

Neurological disorders, marked by progressive neuronal degeneration, impair essential cognitive functions like memory and motor coordination… This manuscript explores the significant roles of glial cell line-derived neurotrophic factor (GDNF), its co-receptors (GFRA1), and the receptor tyrosine kinase (RET) in mediating neuronal survival and function in various neurodegenerative conditions. The interplay between pivotal signaling pathways—PI3K/AKT and ERK1/2—facilitated by GDNF/GFRA1/RET, is emphasized for its neuroprotective effects. Dysregulation of these pathways is implicated in neurodegenerative and neuropsychiatric processes, with overactivation of GSK3β contributing to neuronal damage and apoptosis. Experimental evidence supports that activation of the RET receptor by GDNF enhances AKT signaling, promoting cell survival by inhibiting apoptotic pathways—therapeutic strategies incorporating GDNF delivery and RET activation present promising neuronal protection and regeneration options. Furthermore, inhibition of GSK3β demonstrates potential in ameliorating tau-related pathologies, while small molecule RET agonists may enhance therapeutic efficacy. This review explores the knowledge of GDNF/GFRA1/RET and PI3K/AKT/ERK1/2 associated signaling cascades, underscoring their significance in neuroprotection and therapeutic targeting to combat neurodegenerative diseases. Emerging approaches such as gene therapy and small-molecule RET agonists may offer novel avenues for treatment, although challenges like targeted delivery across the blood-brain barrier remain pertinent.

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来源期刊

Neuropeptides 医学-内分泌学与代谢

CiteScore

5.40

自引率

6.90%

发文量

审稿时长

>12 weeks

期刊介绍： The aim of Neuropeptides is the rapid publication of original research and review articles, dealing with the structure, distribution, actions and functions of peptides in the central and peripheral nervous systems. The explosion of research activity in this field has led to the identification of numerous naturally occurring endogenous peptides which act as neurotransmitters, neuromodulators, or trophic factors, to mediate nervous system functions. Increasing numbers of non-peptide ligands of neuropeptide receptors have been developed, which act as agonists or antagonists in peptidergic systems. The journal provides a unique opportunity of integrating the many disciplines involved in all neuropeptide research. The journal publishes articles on all aspects of the neuropeptide field, with particular emphasis on gene regulation of peptide expression, peptide receptor subtypes, transgenic and knockout mice with mutations in genes for neuropeptides and peptide receptors, neuroanatomy, physiology, behaviour, neurotrophic factors, preclinical drug evaluation, clinical studies, and clinical trials.