Parkinson´s disease (PD) is a neurodegenerative disorder, in which dopamine (DA) neurons degenerate in substantia nigra and no cure exists. We have discovered cerebral dopamine neurotrophic factor (CDNF) that protects and restores the function of DA neurons in animal models of PD together with homologous MANF forming an evolutionarily conserved family of unconventional neurotrophic factors with unique structure and mode of action. In collaboration with Finnish company Herantis Pharma CDNF was tested in phase I–II clinical trial in PD patients showing that CDNF is safe and has therapeutic effect. Thus, CDNF may revolutionize PD therapy, but the molecular mechanisms of action of CDNF and MANF, as well as their receptors and signalling pathways are still unknown. Therefore, the main aim of this proposal is to identify CDNF and MANF receptors, to characterize their signalling pathways and solve the crystal structures of the CDNF-and MANF in the complex with their receptors.

2021

2025