Fundamental research and practical application of GDNF as a neuroprotective agent in neurodegenerative diseases

Glial cell line-derived neurotrophic factor (GDNF) is under extensive investigation as a therapeutic agent for treating age-related neurodegenerative diseases and traumatic neuronal injury. The compelling results from preclinical studies contrast with the disappointing outcomes of phase II clinical trials in Parkinson’s disease, highlighting the need for further fundamental research. Several hypotheses have been proposed to explain these discrepancies, including challenges with the delivery of high molecular weight drugs, GDNF’s high affinity for heparin and heparin-like molecules, which limits its biodistribution in the brain parenchyma, the use of protein forms differing from the native GDNF, and the existence of multiple isoforms of the protein. These issues underscore the necessity for further investigation into GDNF at the genetic, RNA, and protein levels. This review aims to consolidate the latest data on GDNF, address the challenges identified, and explore its potential for therapeutic application in human neurodegenerative diseases.