The Molecular Pathway of p75 Neurotrophin Receptor (p75NTR) in Parkinson's Disease: The Way of New Inroads.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease of the brain. PD is characterized by motor and non-motor symptoms. The p75 neurotrophin receptor (p75NTR) is a functional receptor for different growth factors including pro-brain derived neurotrophic factor (pro-BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Consequently, this review aimed to illustrate the detrimental and beneficial role of p75NTR in PD. Diverse studies showed that p75NTR and its downstream signaling are intricate in the pathogenesis of PD. Nevertheless, pro-apoptotic and pro-survival pathways mediated by p75NTR in PD were not fully clarified. Of note, p75NTR plays a critical role in the regulation of dopaminergic neuronal survival and apoptosis in the CNS. Particularly, p75NTR can induce selective apoptosis of dopaminergic neurons and progression of PD. In addition, p75NTR signaling inhibits the expression of transcription factors which are essential for the survival of dopaminergic neurons. Also, p75NTR expression is connected with the severity of dopaminergic neuronal injury. These verdicts implicate p75NTR signaling in the pathogenesis of PD, though the underlying mechanistic pathways remain not elucidated. Collectively, the p75NTR signaling pathway induces a double-sword effect either detrimental or beneficial depending on the ligands and status of PD neuropathology. Therefore, p75NTR signaling seems to be protective via phosphoinositide 3-kinase (PI3K)/AKT and Bcl-2 and harmful via activation of JNK, caspase 3, nuclear factor kappa B (NF-κB), and RhoA pathways.