Expression Of MHC-Ⅰ In Dopaminergic Neurons Induces Autoimmune Activation In MPTP Model Of Parkinson’s Disease Model

BACKGROUD:Parkinson’s disease(PD)is one of the most common neurodegenerative disease.Its pathology are the formation of Lewy bodies in dopaminergic neurons and the degeneration of dopaminergic neurons in substantia nigra.Its clinical symptoms are resting tremor,bradykinesia and dystonia.Previously,the cause of Parkinson’s disease is considered to be associated with mitochondrial dysfunction,genetic abnormalities,neuron inflammation,and environmental factors.In recent years,more and more evidences have pointed out that autoimmunity may also plays an essential role in the cause of Parkinson’s disease,in a way of autoimmune activation which may result in apoptosis of dopaminergic neurons.In autoimmunity,MHC-Ⅰ plays a key role as an antigen-presenting protein.The cells expressing MHC-Ⅰ can be recognized by the T cells and then be attacked,resulting in cells apoptosis.However,in the central nervous system(CNS),MHC-Ⅰ only expresses in the embryonic stage,mainly relating to the synaptic plasticity of neurons,and participates in the development of the CNS.In recent years,studies found that catecholaminergic neurons expressed MHC-Ⅰ in adult’s substantia nigra but no MHC-Ⅰ expression in noncatecholaminergic neurons,indicating the MHC-Ⅰ expression involved in the progression of PD.Perhaps it’s the expression of MHC-Ⅰ that rendered the dopaminergic neurons susceptible to the immune cells and caused the neuron degeneration.OBJECT:1、Study whether neurons would present MHC-Ⅰ in PD model.2、Is the presentation of antigen by MHC-Ⅰ in dopaminergic neurons induce autoimmune activation in PD model?3、Explore the possible mechanism of antigen presentation of dopaminergic neurons.METHOD:1、SH-SY5Y cells were treated with mpp+to establish the PD cell model,to observe the expression of MHC-Ⅰ,which indirectly reveal the antigen presentation in the cells.2、Mice were injected imtraperitoneally with MPTP to build a PD murine model,in order to determine whether the antigen presentation of dopaminergic neurons was agreed with cell experiments.Furthermore,immunofluorescence was used to observe whether the expression of MHC-Ⅰ in dopaminergic neurons induced CD8+T cell lifiltration and autoimmune activation.We also repressed the neuron expressing MHC-Ⅰ in SN by Stereotactic injection of adenovirus,to detect if it could reduce the autoimmune activation in oxidative stress.3、In immune cells,mitochondrial antigen presentation is associated with Parkinson’s related protein PINK1.We knockdown the PINK1 protein in SH-SY5Y,and then treated with mpp+to detect whether antigen presentation increased.RESULT:1、In the PD model,the expression of MHC-Ⅰ in dopaminergic neurons increased in the level of gene expression and protein expression.As for the control groups the expression of MHC-Ⅰ was nearly undetectable.2、In PD model murine,it was observed that the MPTP-treated mouse expressed MHC-Ⅰ in dopaminergic neurons,while non-MPTP-treated mice did not present MHC-Ⅰ in dopaminergic neurons.Moreover,there were CD8+T cell infiltration in PD model mice,and in control group the cytotoxic T cell infiltration was not detectable.After knocking down the expression of MHC-Ⅰ,CD8+T cell infiltration was reduced,and the apoptosis of dopaminergic neurons was also reduced.3、In SH-SY5Y cells which PINK1 protein were knocked down,the expression of MHC-Ⅰ increased,more than the negative control groups in mpp+treated PD model.CONCLUSION:1、Neurons do not express MHC-Ⅰ under normal conditions,but in PD model,the expression of MHC-Ⅰ increases.2、Dopaminergic neurons expressing MHC-Ⅰ would active autoimmune attack,and knocked down the expression of MHC-Ⅰ was able to reduce the neuron degeneration in MPTPtreated PD model.3、The antigen presentation of dopaminergic neurons is related to the Parkinson’s disease associated protein PINK1.