Key Subdomains of Cerebral Dopamine Neurotrophic Factor Regulate Its Protective Function in 6-Hydroxydopamine-Lesioned PC12 Cells

Cerebral dopamine neurotrophic factor (CDNF) is a unique neurotrophic factor (NTF) that has shown significant neuroprotective and neurorestorative functions on midbrain dopaminergic neurons. The secondary structure of human CDNF protein contains eight alpha-helices. We previously found that two key helices, alpha 1 and alpha 7, regulated the intracellular trafficking and secretion of CDNF protein in different manners. The alpha 1 mutation (M1) induced most CDNF proteins to reside in the endoplasmic reticulum and little be secreted extracellularly, while the alpha 7 mutation (M7) caused the majority of CDNF proteins to be secreted out of the cells and little reside in the cells. However, the regulation of the two mutants on the function of CDNF remains unclear. In this study, we investigated the effects of M1 and M7 on the protective activity of CDNF in PC12 cells, which were treated with 6-hydroxydopamine (6-OHDA) to mimic Parkinson's disease. We found that both M1 and M7 could promote survival and inhibit apoptosis more effectively than Wt in 6-OHDA-lesioned PC12 cells. Therefore, these findings will advance our understanding of the important regulation of subdomains on the function of NTFs.