Parkinson＇s disease （PD） is pathologically characterized by the presence of α-synuclein （α-syn）-positive intra-cytoplasmic inclusions named Lewy bodies in the dopaminergic neurons of the substantia nigra. A series of morbid consequences are caused by pathologically high amounts or mutant forms of α-syn, such as defects of membrane trafficking and lipid metabolism. In this review, we consider evidence that both point mutation and overexpression of α-syn result in aberrant degradation in neurons and microglia, and this is associated with the autophagy-lysosome pathway and endosome-lysosome system, leading directly to pathological intracellular aggregation, abnormal externalization and re-internalization cycling （and, in turn, internalization and re-externalization）, and exocytosis. Based on these pathological changes, an increasing number of researchers have focused on these new therapeutic targets, aiming at alleviating the pathological accumulation of α-syn and re-establishing normal degradation.
Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood.The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)mouse model of Parkinson’s disease(PD).The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model.Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment.JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis.These pro-apoptosis effect can be diminished by curcumin.Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP.Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients.
SK channels are small conductance calcium-activated potassium channels that are widely expressed in different neurons with distinct subtypes.They play an important role in modulating synaptic plasticity,dopaminergic neurotransmission, and learning and memory.The present review was mainly focused on the recent findings on the contradictory roles of SK channels in modulating dopaminergic neurons in substantia nigra and in the pathogenesis of Parkinson＇s disease （PD） . Besides,whether modulation of SK channels could be a potential target for PD treatment was also discussed.
The growth factor receptor-bound protein 2 （Grb2） -associated binder （Gab） proteins are intracellular scaffolding/ docking molecules,and participate in multiple signaling pathways,usually acting as the downstream effector of protein-tyrosine kinases （PTKs） -triggered signal transduction pathway.When phosphorylated by PTKs,Gab proteins can recruit several signaling molecules （p85,SHP2,and Crk） ,and subsequently activate multiple transmitting signals that are critical for cell growth,survival,differentiation and apoptosis.Recently,it has been reported that Gab2 polymorphism is associated with the increase in the risk of Alzheimer’s disease （AD） and is involved in the pathogenesis of AD.This review mainly focuses on the structure and function of Gab2 protein and its role in the pathogenesis of AD.
