TMEM106B Knockdown Exhibits a Neuroprotective Effect in Parkinson's Disease via Decreasing Inflammation and Iron Deposition.

Parkinson's disease (PD) is closely related to iron accumulation and inflammation. Emerging evidence indicates that TMEM106B plays an essential role in PD. But whether TMEM106B could act on neuroinflammation and iron metabolism in PD has not yet been investigated. The aim of this study was to investigate the pathological mechanisms of inflammation and iron metabolism of TMEM106B in PD. 1-methyl-4-phenylpyridinium (MPP+)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced SH-SY5Y cells and mice were treated with LV-shTMEM106B and AAV-shTMEM106B to construct PD cellular and mouse models. Pole tests and open-field test (OFT) were performed to evaluate the locomotion of the mice. Immunohistochemistry and iron staining were used to detect TH expression and iron deposition in the SN. Iron staining was used to measure the levels of iron. Western blotting was used to detect the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)), NOD-like receptor protein 3 (NLRP3) inflammasome, divalent metal transporter 1 (DMT1), and Ferroportin1 (FPN1)). Knockdown of TMEM106B improved motor ability and rescued dopaminergic (DA) neuron loss. TMEM106B knockdown attenuated the increases of TNF-α, IL-6, NLRP3 inflammasome, and DMT1 expression in the MPP+ and MPTP-induced PD models. Furthermore, TMEM106B knockdown also increases the expression of FPN1. This study provides the first evidence that knockdown of TMEM106B prevents dopaminergic neurodegeneration by modulating neuroinflammation and iron metabolism.

P2X4 receptor participates in autophagy regulation in Parkinson's disease.

Dysfunctional autophagy often occurs during the development of neurodegenerative diseases, such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia, astrocytes, and neurons of the central and peripheral nervous systems. P2X4R is involved in the regulation of cellular excitability, synaptic transmission, and neuroinflammation. However, the role played by P2X4R in Parkinson's disease remains poorly understood. Rat models of Parkinson's disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta. P2X4R-targeted small interfering RNA (siRNA) was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor. The results showed that the inhibition of P2X4 receptor expression in Parkinson's disease model rats reduced the rotation behavior induced by apomorphine treatment, increased the latency on the rotarod test, and upregulated the expression of tyrosine hydroxylase, brain-derived neurotrophic factor, LC3-II/LC3-I, Beclin-1, and phosphorylated tropomyosin receptor kinase B (TrkB) in brain tissue, while simultaneously reducing p62 levels. These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway, leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy. These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson's disease. This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University (approval No. QYFYWZLL26119) on April 12, 2016.

P2X4R Overexpression Upregulates Interleukin-6 and Exacerbates 6-OHDA-Induced Dopaminergic Degeneration in a Rat Model of PD.

The pathogenesis of Parkinson's disease (PD) remains elusive. Current thinking suggests that the activation of microglia and the subsequent release of inflammatory factors, including interleukin-6 (IL-6), are involved in the pathogenesis of PD. P2X4 receptor (P2X4R) is a member of the P2X superfamily of ion channels activated by ATP. To study the possible effect of the ATP-P2X4R signal axis on IL-6 in PD, lentivirus carrying the P2X4R-overexpression gene or empty vector was injected into the substantia nigra (SN) of rats, followed by treatment of 6-hydroxydopamine (6-OHDA) or saline 1 week later. The research found the relative expression of P2X4R in the 6-OHDA-induced PD rat models was notably higher than that in the normal. And P2X4R overexpression could upregulate the expression of IL-6, reduce the amount of dopaminergic (DA) neurons in the SN of PD rats, suggesting that P2X4R may mediate the production of IL-6 to damage DA neurons in the SN. Our data revealed the important role of P2X4R in modulating IL-6, which leads to neuroinflammation involved in PD pathogenesis.

Association between vitamin D receptor polymorphisms and susceptibility to Parkinson's disease: An updated meta-analysis.

The relationships between vitamin D receptor (VDR) gene polymorphisms, particularly ApaI, BsmI, FokI, and TaqI, and Parkinson's disease (PD) has received increasing attention in the research community. However, as the results yielded by this increased research have hitherto conflicted, we performed an updated meta-analysis of reports on the relationships between VDR polymorphisms and PD published before October 2019 that we collected from the PUBMED, EMBASE, EBSCO, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The ten articles that met our screening criteria included 2782 patients and 3194 healthy controls. All the data that we received were analyzed with Stata 12.0 statistical software. The odds ratio (OR) and 95 % confidence intervals (CIs) were used to determine the relationship between VDR gene diversity and PD. While we did not find a significant correlation between the ApaI, BsmI, and TaqI polymorphisms and the risk of PD in any of the considered genetic models, we found a clear association between the FokI polymorphism and susceptibility to PD (C vs. T: OR = 1.246, 95 % CI: 1.101-1.411, P = 0; CC vs. TT: OR = 1.630, 95 % CI: 1.243-2.139, P = 0; CT vs. TT: OR = 1.382, 95 % CI: 1.059-1.804, P = 0.017; CC + CT vs. TT: OR = 1.491, 95 % CI: 1.159-1.919,P = 0.002; CC vs. CT + TT: OR = 1.261, 95 % CI: 1.062-1.496, P = 0.008). Our subgroup analysis performed according to ethnicity revealed that FokI increased the risk of PD in Asian populations (C vs. T: OR = 1.261, 95 % CI: 1.080-1.472, P = 0.003; CC vs. TT: OR = 1.664, 95 % CI: 1.189-2.330, P = 0.003; CT vs.TT: OR = 1.387, 95 % CI: 1.000-1.925, P = 0.05; CC + CT vs. TT: OR = 1.497, 95 % CI: 1.098-2.042, P = 0.011; CC vs. CT + TT: OR = 1.285, 95 % CI: 1.036-1.593, P = 0.022). Overall, the gene polymorphism of FokI only increases the risk of PD among Asian populations. Given the limited sample size of this study, the findings should be carefully explained.