GFRA1

Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1), also known as GDNFR-alpha1 or RET co-receptor, is a glycosylphosphatidylinositol (GPI)-anchored cell surface protein that binds GDNF with high affinity. It functions as a ligand-binding subunit for the RET receptor tyrosine kinase, forming a ternary complex to activate downstream signaling cascades including PI3K/AKT, MAPK/ERK, and PLCγ pathways. These pathways regulate neuronal survival, differentiation, and maintenance, particularly in the enteric nervous system and dopaminergic neurons. GFRA1 mutations are implicated in Hirschsprung disease, Parkinson's disease, and neuroendocrine tumors. Therapeutic strategies targeting the GDNF-GFRA1-RET axis, such as RET inhibitors (e.g., selpercatinib) and GDNF mimetics, are under clinical evaluation for neurodegenerative disorders and RET-driven cancers. Recent phase III trials of gene therapy delivering GDNF in Parkinson's patients showed mixed efficacy, highlighting pathway complexity.