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The prevalence of neurodegenerative diseases is a significant challenge in modern healthcare. The rapid growth rate, accompanied by the degeneration of nerve cells, emphasizes the importance of developing new treatment methods and identifying biomarkers for early-stage detection. Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), play a crucial role in maintaining nerve and glial cell health, as well as in neurogenesis and synaptogenesis. GDNF provides protective effects for dopaminergic, noradrenergic, and gamma-aminobutyric acid neurons, as well as motor neurons, making it an important target for research into the pathogenesis and treatment of neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. A number of translational studies have confirmed GDNF therapeutic potential in relation to the treatment of neurodegeneration. Despite the promising results from preclinical trials, neurotrophic factors have not yet realized their potential as a neurodevelopmental therapy in clinical studies. The challenges in GDNF clinical trials may stem from the need to consider the intervention stage, evaluate the functional activity of signaling pathways, and enhance the effectiveness of targeted factor delivery. This review will outline the mechanisms of GDNF action, analyze changes in neurotrophic factor levels in central and peripheral tissues in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and present recent advances in GDNF-based therapies for neurodegenerative disorders. Through a critical analysis of these findings, the review supports shifting the GDNF therapy paradigm from simple substitution to modulating the molecule's signaling pathways during the early disease stages, employing modern targeted approaches such as nanotherapy.