Interaction between glial-cell-line-derived neurotrophic factor (GDNF) and 2-O-sulphated heparin-related glycosaminoglycans.

Glial cell line-derived growth factor (GDNF) is a cytokine of the transforming growth factor (TGF)-beta family with potent neuroprotective activity. Clinical trials of recombinant GDNF in advanced Parkinson's disease are currently under way. It is known that mice homozygous for disruption of the gene encoding heparan sulphate 2-O-sulphotransferase die perinatally, due to the complete absence of kidneys. Similar phenotypes arise from targeted disruption of the genes encoding either GDNF, or its receptors, GFRalpha1 and c-Ret. It may therefore be proposed that GDNF normally binds to 2-O-sulphate-rich heparan sulphate within kidney progenitor tissues, and that this interaction is essential for its activity in kidney development. In support of this hypothesis we have shown in ELISA studies that GNDF binds to heparin and heparan sulphate. This binding is unusually sensitive to the chemical 2-O-desulphation, and promotes the binding of GNDF to GFRalpha1.