Glial-derived neurotrophic factor (GDNF) is a member of the TGF-β superfamily. GDNF signals through a multi-component receptor system, composed of a RET protooncogene and one of the four α1-α4 receptors¹.

GDNF promotes survival of various neuronal cells, including motoneurons^2,3, Purkinje cells and sympathetic neurons⁴. In embryonic midbrain cultures, GDNF promotes the survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake⁵. Cells that express GDNF include Sertoli cells, type 1 astrocytes, Schwann cells⁶, neurons, pinealocytes, and skeletal muscle cells⁷.

In vivo, following transection of facial motor neuron axons, locally applied GDNF has been shown to rescue virtually all damaged neurons from death⁸. GDNF may be of clinical relevance in the treatment of Parkinson's disease that is characterized by progressive degeneration of midbrain dopaminergic neurons^9,10.

Recently, it has been hypothesized that functional, carboxy-terminally amidated peptides are processed from the GDNF precursor upon proteolytic cleavage by furin-like endopeptidase^11,12,13. Those different peptides (a 5-mer and 11-mer) have not been isolated endogenously to date. However, the rat 11-mer sequence (named brain excitatory peptide, BEP) significantly induced synaptic excitability and possessed some dopaminergic activities in vitro (thus named dopamine neuron stimulating peptides, DNSP)¹³. Furthermore, the human 11-mer sequence (named DNSP-11) exhibits neurotrophic-like properties¹³.

Thus, the role of the full proDomain of GDNF, which is a product of proteolytic cleavage of proGDNF, is not clearly understood yet.