Cerebral dopamine neurotrophic factor (CDNF) and Parkinson’s disease: Behavioural and clinical investigations

Abstract

Parkinson’s disease (PD) is among the most devastating neurodegenerative disorders, and affects 1% of the global population above the age of 60. Several mechanisms have been proposed to explain the dopamine degeneration exhibited in PD: mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Inaccurate diagnosis is one of the greatest challenges to treatment of PD. Currently, there is no standard diagnostic test for PD. Neurotrophic factors (NTF) are secreted proteins that promote survival and maintenance of neurons during development. The loss of NTFs for specific neuronal populations could confer susceptibility to various neurodegenerative disorders. Cerebral dopamine neurotrophic factor (CDNF) is a novel NTF selective for dopamine neurons. CDNF has demonstrated profound neuroprotective and neurorestorative effects on dopamine neurons in well established animal models of PD. Presently, there are no studies examining endogenous levels of CDNF in PD models or clinical populations of PD, prompting the present study. Findings will bring insight into the neurobiological mechanisms underlying neurodegeneration in PD. This study has determined that CDNF protein and mRNA expression is not altered following 6-OHDA lesioning, suggesting a compensatory mechanism of CDNF in response to injury. We have also determined that CDNF mRNA expression declines with age, which could confer susceptibility to developing neurodegenerative diseases such as PD. In clinical populations of PD, platelets showed a significant increase in CDNF mRNA expression that was not seen in lymphocytes or whole blood. This suggests a role of CDNF in PD, specifically for platelets; however, it is important to delineate whether this increase is the result of treatment. Incidentally, we found that CDNF mRNA expression is significantly reduced following stroke. Together, these results stress the importance of CDNF in disorders stemming from ER stress. Future studies should examine the role of CDNF in preclinical models of stroke, as well as knockout models of PD.