Dopamine Agonists Exert Nurrl-inducing Effect in Peripheral Blood Mononuclear Cells of Patients with Parkinson＇s Disease

Background： Nurrl plays an essential role in the development, survival, and function maintenance ofmidbrain dopaminergic （DA） neurons, and it is a potential target for Parkinson＇s disease （PD）. Nurrl mRNA can be detected in peripheral blood mononuclear cells （PBMCs）, but whether there is any association of altered Nurrl expression in PBMC with the disease and DA drug treatments remains elusive. This study aimed to measure the Nurrl mRNA level in PBMC and evaluate the effect of Nurrl expression by DA agents in vivo and in vitro. Methods： The mRNA levels of Nurrl in PBMC of four subgroups of 362 PD patients and 193 healthy controls （HCs） using real-time polymerase chain reaction were measured. The nonparametric Mann-Whitney U-test and Kruskal-Wallis test were performed to evaluate the differences between PD and HC, as well as the subgroups of PD. Multivariate linear regression analysis was used to evaluate the independent association of Nurrl expression with Hoehn and Yahr scale, age, and drug treatments. Besides, the Nurrl expression in cultured PBMC was measured to determine whether DA agonist pramipexole affects its mRNA level. Results： The relative Nurrl mRNA levels in DA agonists treated subgroup were significant higher than those in recent-onset cases without any anti-PD treatments （de novo） （P 〈 0.001 ） and HC groups （P 〈 0.010）, respectively. Furthermore, the increase in Nurr I mRNA expression was seen in DA agonist and L-dopa group. Multivariate linear regression showed DA agonists, L-dopa, and DA agonists were independent predictors correlated with Nurrl mRNA expression level in PBMC. In vitlv, in the cultured PBMC treated with 10 μmol/L pramipexole, the Nurrl mRNA levels were significantly increased by 99.61%, 71.75%, 73.16% in 2, 4, and 8 h, respectively （P 〈 0.001 ）. Conclusions： DA agonists can induce Nurrl expression in PBMC, and such effect may contribute to DA agonists-mediated neuroprotection on DA neurons.

Association Analysis of Proteasome Subunits and Transporter Associated with Antigen Processing on Chinese Patients with Parkinson＇s Disease

Background： Proteasome subunits （PSMB） and transporter associated with antigen processing （TAP） loci are located in the human leukocyte antigen （HLA） Class I1 region play important roles in immune response and protein degradation in neurodegenerative diseases. This study aimed to explore the association between single nucleotide polymorphisms （SNPs） of PSMB and TAP and Parkinson＇s disease （PD）. Methods： A case-control study was conducted by genotyping SNPs in PSMB8, PSMBg, TAP1, and TAP2 genes in the Chinese population. Subjects included 542 sporadic patients with PD and 674 healthy controls. Nine identified SNPs in PSMB8, PSMBg, TAP1, and TAP2 were genotyped through SNaPshot testing. Results： The stratified analysis ofrs 17587 was specially performed on gender. Data revealed that female patients carry a higher frequency of rsl7587-G/G versus （A/A ＋ G/A） compared with controls. But there was no significant difference with respect to the genotypic frequencies of the SNPs in PSMB8, TAP1, and TAP2 loci in PD patients. Conclusion： Chinese females carrying the rs 17587-G/G genotype in PSMB9 may increase a higher risk for PD, but no linkage was found between other SNPs in HLA Class II region and PD.

Dopaminergic neurons show increased low-molecular-mass protein 7 activity induced by 6-hydroxydopamine in vitro and in vivo

Background:Abnormal expression of major histocompatibility complex class I(MHC-I)is increased in dopaminergic(DA)neurons in the substantia nigra(SN)in Parkinson’s disease(PD).Low-molecular-mass protein 7(β5i)is a proteolytic subunit of the immunoproteasome that regulates protein degradation and the MHC pathway in immune cells.Methods:In this study,we investigated the role of β5i in DA neurons using a 6-hydroxydopamine(6-OHDA)model in vitro and vivo.Results:We showed that 6-OHDA upregulatedβ5i expression in DA neurons in a concentration-and time-dependent manner.Inhibition and downregulation ofβ5i induced the expression of glucose-regulated protein(Bip)and exacerbated 6-OHDA neurotoxicity in DA neurons.The inhibition of β5i further promoted the activation of Caspase 3-related pathways induced by 6-OHDA.β5i also activated transporter associated with antigen processing 1(TAP1)and promoted MHC-I expression on DA neurons.Conclusion:Taken together,our data suggest that β5i is activated in DA neurons under 6-OHDA treatment and may play a neuroprotective role in PD.