Supramolecular Mimic of Glial Cell Line-Derived Neurotrophic Factor and its Bioactivity on Human Dopaminergic Neurons

The cardinal motor symptoms of Parkinson´s disease (PD) are caused by the degeneration of dopaminergic neurons, making it in principle amenable to treatment by cell replacement therapy. Although this strategy has shown promise in animal models, it has not been as successful in clinical trials. One likely reason for this lack of success is the poor survival of grafted neurons. In animal models, glial cell line-derived neurotrophic factor (GDNF) increases the survival of transplanted dopaminergic neurons, but the ability of GDNF to promote survival is undoubtedly limited by its diffusion away from the graft site and its degradation. We report here on supramolecular nanofibers that display a GDNF-mimetic peptide on their surfaces. This nanostructure mimicked the biological effects of GDNF on human dopaminergic neurons by improving cell survival and promoting morphological, synaptic and electrophysiological maturation, as well as a neuroprotective effect that correlates with the upregulation of genes related to these biological processes. The GDNF nanostructures also enhanced the morphological maturation of human midbrain-like organoids. Thus, the GDNF supramolecular mimic provides a self-assembling matrix that could be delivered in the future with transplanted dopaminergic neurons to enhance their survival and maturation in vivo. Overall design: To evaluate the genes up and downregulated by the GDNF mimic nanostructure, we seeded human-induced pluripotent stem cells-derived dopaminergic neurons on coverslips coated with GDNF mimic nanostructure and compared their relative gene expression changes to scramble GDNF mimic nanostrucutre 4 days after treatment. Gene expression profiling was performed using single-end RNA-Seq data obtained from 3 biological replicates per condition.