Netrin-1/Receptors Regulate The Pathogenesis In Parkinson'S Diseases

The netrins and their receptors (deleted in colorectal cancer [DCC] and unc-5 netrin receptors A-D [UNC5A-D]) play essential roles for central nervous system (CNS) development, mediating axonal and neuronal navigation. Emerging evidence indicates that they are implicated in maintaining the adult brain structure and mediating the pathogenesis of Parkinson's disease (PD). Recently, we reported the reduction of netrin-1 and brain-derived neurotrophic factor (BDNF) was inversely correlated with inflammatory cytokines-activated transcription factor CCAAT/enhancer binding protein beta (C/EBP beta) in PD patient brains and colons. C/EBP beta binds to the promoters, repressing both netrin-1 and BDNF mRNA expression. Remarkably, netrin-1 deprivation triggered mammalian Ste20-like kinases 1 (MST1; Hippo) activation, which subsequently phosphorylated UNC5B and induced its apoptotic fragmentation via active caspase-3 in dopaminergic neurons in the substantia nigra (SN). Moreover, deficiency of netrin-1 stimulated activation of delta-secretase (asparagine endopeptidase [AEP]) that cleaves alpha-Syn at N103 and UNC5C receptor, facilitating PD pathologies. This review summarizes our current understanding of the crucial role of netrin-1 and its receptors in CNS and enteric nervous system contributing to PD pathologies by orchestrating multiple molecular players, including MST1, AEP, and C/EBP beta. These findings support that blockade of AEP or stimulation of netrin-1 signaling may provide an innovative disease-modifying therapeutic strategy for treating PD.