The emerging portrait of GDNF: A small neuroinductive isoform named djGDNF47

Glial cell line-derived neurotrophic factor (GDNF) is a highly conserved neurotrophic factor that is critical for organismal development and survival. GDNF is known for promoting the survival and differentiation of dopaminergic neurons, preventing apoptosis in mature neurons. These properties make GDNF a candidate for therapeutic applications, particularly in neurodegenerative diseases such as Parkinson's disease (PD). Despite promising preclinical results in rodent and non-human primate models, clinical trials have failed to replicate these findings, necessitating further investigation into the underlying causes. In prior studies, our team developed a chimeric mGDNF/GFP protein with notable neuroinductive properties. However, further characterization of mGDNF, excluding GFP, led to the discovery of alternative transcript variants, resulting in the identification of several small peptides. Among them, the peptide djGDNF47 (47shGDNF) demonstrated neuroinductive activity in vitro on cell models of the PC12 line and dorsal embryonic ganglia. This activity was observed both when synthesized in transgenic HEK293 cells expressing the cloned djGDNF47 and in the form of a synthesized analog. This finding suggests the existence of alternative splicing mechanisms that generate short neurotrophic peptides. Our current research focuses on djGDNF47 (47shGDNF), a bioactive GDNF peptide with promising therapeutic potential for treating neurodegenerative diseases such as PD.