Shaogang Qu

The biomarkers of immune dysregulation and inflammation response in Parkinson disease

Parkinson’s disease (PD) is referring to the multi-systemic α-synucleinopathy with Lewy bodies deposited in midbrain. In ageing, the environmental and genetic factors work together and overactive major histocompatibility complex pathway to regulate immune reactions in central nerve system which resulting in neural degeneration, especially in dopaminergic neurons. As a series of biomarkers, the human leukocyte antigen genes with its related proteomics play cortical roles on the antigen presentation of major histocompatibility complex molecules to stimulate the differentiation of T lymphocytes and i-proteasome activities under their immune response to the PD-related environmental alteration and genetic variation. Furthermore, dopaminergic drugs change the biological characteristic of T lymphatic cells, affect the α-synuclein presentation pathway, and inhibit T lymphatic cells to release cytotoxicity in PD development. Taking together, the serum inflammatory factors and blood T cells are involved in the immune dysregulation of PD and inspected as the potential clinic biomarkers for PD prediction.

Enhancing Beta-Catenin Activity via GSK3beta Inhibition Protects PC12 Cells against Rotenone Toxicity through Nurr1 Induction.

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta. Increasing evidence showed that Wnt/β-catenin pathway and the orphan nuclear receptor Nurr1 play crucial roles in the survival and functional maintenance of DA neurons in the midbrain and GSK-3β antagonists LiCl and SB216763 were used to activate Wnt/β-catenin pathway experimentally. However, the detail mechanism underlying the neuroprotection against apoptosis on DA neuron is still unclear and the interaction between Wnt/β-catenin and Nurr1 remains undisclosed. In this study, using cell biological assay we investigated the function of Wnt/β-catenin and its crosstalk with Nurr1 on the course of PC12 cell degeneration in vitro. Our data showed that PC12 cell viability was inhibited by rotenone, but attenuated by GSK-3β antagonists LiCl or SB216763. The activity of Wnt/β-catenin pathway was deregulated on exposure of rotenone in a concentration-dependent manner. After the interference of β-catenin with siRNA, LiCl or SB216763 failed to protect PC12 cells from apoptosis by the rotenone toxicity. Our data confirmed that Wnt/β-catenin signaling activated by LiCl or SB216763 enhanced Nurr1 expression to 2.75 ± 0.55 and 4.06 ± 0.41 folds respectively compared with control detected by real-time PCR and the interaction of β-catenin with Nurr1 was identified by co-immunoprecipitate analysis. In conclusion, the data suggested that Wnt/β-catenin and Nurr1 are crucial factors in the survival of DA neurons, and the activation of Wnt/β-catenin pathway exerts protective effects on DA neurons partly by mean of a co-active pattern with Nurr1. This finding may shed a light on the potential treatment of Parkinson disease.

Iron promotes α-synuclein aggregation and transmission by inhibiting TFEB-mediated autophagosome-lysosome fusion

Recent studies have strongly shown that cell‐to‐cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α‐synuclein remains unclear. Here, we constructed a cell‐to‐cell transmission model of α‐synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl2, and α‐synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or over‐expression. Our results demonstrated that iron promoted α‐synuclein aggregation and transmission by inhibiting autophagosome‐lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB (TFEB), a master transcriptional regulator of autophagosome‐lysosome fusion, and inhibited its nuclear translocation through activating AKT/mTORC1 signaling. After silencing TFEB, ratios of α‐synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was over‐expressed, the transmission of α‐synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α‐synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and α‐synuclein, and identify TFEB as not only a potential target for preventing α‐synuclein transmission, but also a critical factor for iron‐induced α‐synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α‐synuclein transmission in Parkinsons disease.

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 II 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 Parkinsons disease (PD). Methods:A case–control study was conducted by genotyping SNPs in PSMB8, PSMB9, TAP1, and TAP2 genes in the Chinese population. Subjects included 542 sporadic patients with PD and 674 healthy controls. Nine identified SNPs in PSMB8, PSMB9, TAP1, and TAP2 were genotyped through SNaPshot testing. Results:The stratified analysis of rs17587 was specially performed on gender. Data revealed that female patients carry a higher frequency of rs17587-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 rs17587-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.

Astrocytic glutamatergic transporters are involved in Aβ-induced synaptic dysfunction

In Alzheimers disease (AD), dementia severity correlates most strongly with decreased synapse density in the hippocampus and cerebral cortex. Although studies in rodents have established that hippocampal long-term potentiation (LTP) is inhibited by soluble oligomers of beta-amyloid (Aβ), the synaptic mechanisms remain unclear. Here, field excitatory postsynaptic potentials (fEPSP) recordings were made in the CA1 region of mouse hippocampal slices. The medium of APP-expressing CHO cells, which contain soluble forms of Aβ including small oligomers, inhibited LTP and facilitated long-term depression (LTD), thus making the LTP/LTD curve shift toward the right. This phenomenon could be mimicked by the non-selective glutamate transporter inhibitor, DL-TBOA. More specifically, the Aβ impaired LTP and facilitated LTD were occluded by the selective astrocytic glutamate transporter inhibitors, TFB-TBOA. In cultured astrocytes, the Aβ oligomers also decrease astrocytic glutamate transporters (EAAT1, EAAT2) expression. We conclude that soluble Aβ oligomers decrease the activation of astrocytic glutamate transporters, thereby impairing synaptic plasticity.

Association of DNMT3b gene variants with sporadic Parkinson's disease in a Chinese Han population

Parkinsons disease (PD) is the second most common neurodegenerative disorder worldwide. Epigenetic modifications, specifically DNA methylation, have been implicated in the development of this disease. Genetic variants of DNA methyltransferase 3b (DNMT3b), one of the most important DNA methyltransferases, were shown to be associated with PD in a Brazilian population. However, it is unclear whether genetic variants of DNMT3b increase the risk of PD in the Chinese Han people. The present study aimed to investigate the association of the DNMT3b variants rs2424913, rs998382 and rs2424932 with PD in a Chinese Han population.

Association of IGF1 gene polymorphism with Parkinson's disease in a Han Chinese population

Accumulating evidence suggests that insulin‐like growth factor 1 (IGF1) plays an important role in Parkinsons disease (PD) pathogenesis. However, it is not clear whether IGF1 polymorphism contributes to PD risk.

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

BackgroundAbnormal 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.MethodsIn this study, we investigated the role of β5i in DA neurons using a 6-hydroxydopamine (6-OHDA) model in vitro and vivo.ResultsWe showed that 6-OHDA upregulated β5i expression in DA neurons in a concentration- and time-dependent manner. Inhibition and downregulation of β5i 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.ConclusionTaken together, our data suggest that β5i is activated in DA neurons under 6-OHDA treatment and may play a neuroprotective role in PD.

Gene Dysfunction Mediates Immune Response to Dopaminergic Degeneration in Parkinson’s Disease

Many publications reported that genetic dysfunction mediates abnormal immune responses in the brain, which is important for the development of neurodegenerative diseases, especially for Parkinsons disease (PD). This immune disorder results in subsequent inflammatory reaction, which stimulates microglia or other immune cells to secrete cytokines and chemokines and disturbs the proportion of peripheral blood lymphocyte subsets contributing to dopaminergic (DA) neuron apoptosis. Furthermore, the abnormal immune related signal pathways caused by genetic variants promote chronic inflammation destroying the blood-brain barrier, which allows infiltration of different molecules and blood cells into the central nervous system (CNS) exerting toxicity on DA neurons. As a result, the inflammatory reaction in the CNS accelerates the progression of Parkinsons disease and promotes α-synuclein aggregation and diffusion among DA neurons in the procession of Parkinsons disease. Thus, for disease evaluation, the genetic mediated abnormal immune response in PD may be assessed based on the multiple immune molecules and inflammatory factors, as well as the ratio of lymphocyte subsets from PD patients peripheral blood as potential biomarkers.