This grant builds upon the research from a prior grant: CDNF a novel conserved neurotrophic factor that protects midbrain dopaminergic neurons in vivo
Promising Outcomes of Original Grant:
Future treatment of Parkinson’s disease aim at therapies which would stop the progress of the disease and restore the function of injured dopamine nerves in the brain. We have recently discovered a novel neurotrophic factor, called Conserved Dopamine Neurotrophic Factor (CDNF). CDNF protects and repairs dopamine neurons in a neurotoxin-induced experimental PD model in rats. In this proposal we will study further the effects of CDNF in several models of experimental PD in order to obtain more evidence for its anti Parkinsonian activity.
Objectives for Supplemental Investigation:
We will study the effects of CDNF in mouse MPTP model of PD, as well as in two mouse genetic models of PD, since pre-clinical models of PD represent different mechanisms of dopamine nerve disruption as compared with the 6-OHDA induced model in rats. We also plan to study the effect of chronic infusion of CDNF in rat PD model, which will give us information about CDNF efficacy and safety. Together with our previous results, these experiments give a better insight to the anti parkinsonian activity of CDNF. With these experiments we will also obtain more information of the therapeutic potential of CDNF as a future treatment of PD. To understand the mechanisms of CDNF signaling we plan to characterize and clone the receptor for CDNF. Knowledge on receptor structure is a prerequisite for future discovery of drug substances with CDNF-like activity.
Importance of This Research for the Development of a New PD Therapy:
Neurotrophic factors such as CDNF, GDNF and neurturin are capable of sustaining neurons in the adult brain. In clinical trials, GDNF treatment of Parkinsonian patients resulted in modest clinical improvement and neutralizing GDNF antibodies were detected in some patients. Thus, there is a therapeutic need for new, more selective, better-tolerated neurotrophic factors that could slow down or reverse the progression of PD. Since CDNF seems to be selective for dopamine neurons in the brain, it is an excellent candidate for therapeutic lead in PD.
Final Outcome
MJFF-funded research led to novel findings on the structure and function of new family of neurotrophic factors, the CDNF/MANF – family. We solved the crystal structure of CDNF and MANF and found that these proteins are structurally related, but they may have a different mechanism of action. Both have a saposin-like N-terminal domain that binds lipids, which most likely is responsible for their neuroprotective effect in rodent models of Parkinson’s disease. The C-terminal domains of MANF and CDNF are responsible for their protective effects against cell stress, i.e. endoplasmic reticulum stress, associated with post-ischemic brain damage and neurodegeneration.
We discovered the intracellular receptor of CDNF and MANF, and characterized their mode of action in neurons. CDNF and MANF were neurorestorative in experimental Parkinson’s disease in rats. The mechanism of action of the neurorestorative effect of CDNF is very different from that of GDNF. Another important difference is that the distribution volume of MANF in brain tissue was significantly larger than that of GDNF. The good tissue penetration of MANF is of paramount importance as regards the future use of CDNF and MANF in the therapy of Parkinson’s disease.
This project led to follow-on funding from the Academy of Finland. This funding is for research done in PARKCDNF consortium, part of a European EraNet Neuron consortium to promote research on the role of CDNF as neurorestorative therapy in Parkinson’s disease.
Results of this project were published in the Journal of Comparative Neurology, Current Opinion in Neurobiology, Molecular & Cellular Neurosciences, Proceedings of the National Academy of Sciences, Protein Engineering, Design & Selection and Journal of Neuroscience.