The Effect Of Rasagiline On BAG2and BAG5Protein And Its Dopaminergic Neuroprotecive Effects

Background:Parkinson’s disease (PD) is one of the most common neurodegenerat ive disorder which is characterized by resting tremor, muscle rigidity, balance and posture to reduce obstacles to movement. Characterization of the pathology in PD focused attention on the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of the Lewy body in remaining dopaminergic neurons. Most of these PD patients were sporadic, about10%of these patients were hereditary. The past25years have seen a major expansion of knowledge concerning on the the cause of Parkinson’s disease, though still not clarified, they provide an understanding of environmental and genetic factors that underlie the loss of nigra dopaminergic neurons. Evidence of oxidative stress, mitochondrial dysfunction, abnormal of ubiquitin-depen--dent proteolysis system (UPS), calcium disbalance and inflammation were found on the PD model and corpse of PD patient. Morphology study suggests the loss of neurons in PD patient mainly in three forms: apoptosis, sclerosis, autophagy. Ultra-structure observation of the neurons in SNpc also found the evidence of apoptosis and autophagy.Bcl-2-associated athanogene (BAG)-family proteins were originally identified in the study of the anti-apoptosis protein bcl-2. The BAG proteins are an evolutionarily conserved family proteins distinguished by a common conserved region located near the C terminus termed the BAG domain but differ markedly in their N-terminal regions. The BAG proteins are multifunctional proteins that participate in many physiologic function which contains apoptosis, tumorigenesis, neuron differentiation, stress and cell cycle. BAG family proteins were up-regulated in kinds of tumor and regulate the survival of cells. Previous study demonstrated that BAG family proteins can inhibit cell death by the association with Hsc70/Hsp70or bcl-2. Previous studies observed that BAG2mediate ubiquitin independent degradation of tau through proteasome. BAG5 associated with PINK1and stabilized mitochondrial. All of this indicated that BAG family protein were associated closely with neurodegenerative disease.Rasagiline is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor。This drug has been useful as an anti-Parkinson drug, both in monotherapy and as adjunct to L-Dopa therapy. Unlike other anti-Parkinson drug, Rasagiline can pro-survival dopaminergic neurons. Studies provided the following mechanisms for this function of rasagiline:1) Stabilization of mitochondrial membrane;2) induction of antipoptotic Bcl-2and downregulation of apoptogenic Bad, Bax;3) Induction of GDNF and BDNF;4) Regulation of APP proteolytic processing;5) Activate NF-κB system. Besides, there may be some other binding sites of rasagiline and new possible mechanisms exist.Objective:To research whether BAG family protein were participate in the neuroprotective effect of rasagiline. Methods:1) western-blot and Immunohistochemistry were utilized to analyze the level of BAG1、BAG2、BAG3、BAG5protein in the MPTP-lesion induced PD model of dopaminergic neuron in substantia nigra.2) western-blot and Immunohistochemistry were utilized to analyze the level of BAG2、BAG5protein in the subustantia nigra after Low-dose rasagiline were administrated to the MPTP-lesion induced PD model.Results:1) Western-blot and Immunohistochemistry showed that BAG2and BAG5protein were up-regulated in SNpc of the MPTP PD mouse model.2) Western-blot and Immunohistochemistry showed that BAG2and BAG5protein were further increased when rasagiline was given to MPTP PD mouse model.Conclusion:1) BAG2and BAG5protein participate in Parkinson’s Disease. 2) Rasagiline up-regulate BAG2and BAG5protein and protect opaminergic neurons.