Bidirectional two-sample Mendelian randomization analysis identifies causal associations between oxidative stress and Parkinson's disease.

Background: Observational studies have shown that oxidative stress (OS) is associated with Parkinson's disease (PD). However, whether such observations reflect cause-effect remains largely unknown. To test this, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to investigate the causal-effects between OS biomarkers and PD. Methods: We selected summary statistics data for single-nucleotide polymorphisms (SNPs) associated with catalase (n = 13), glutathione peroxidases (n = 12), superoxide dismutase (n = 13), vitamin A (n = 7), vitamin C (n = 10), vitamin E (n = 12), vitamin B12 (n = 8), folate (n = 14), copper (n = 6), Zinc (n = 7), and iron (n = 23) levels, and the corresponding data for PD from the International Parkinson Disease Genomics Consortium (IPDGC, 33,674 cases and 449,056 controls). Inverse-variance weighted (IVW) MR analyses were conducted to estimate associations of OS with PD. Reverse MR analysis was further performed to predict the causal effects of PD on the above OS biomarkers. Results: As for PD, the IVW method suggested that the Zinc (Zn) levels was significantly associated with PD (OR = 1.107, 95% CI 1.013-1.211; p = 0.025), which is consistent with results from the weighted median analyses. Moreover, the results remained consistent and robust in the sensitivity analysis. However, there were no significant associations of catalase, glutathione peroxidases, superoxide dismutase, vitamin A, vitamin C, vitamin E, vitamin B12, folate, copper, or iron with PD. As for OS, our reverse MR analysis also did not support a causal effect of liability to PD on OS. Conclusion: The MR study supported the causal effect of Zn on PD. These findings may inform prevention strategies and interventions directed toward OS and PD.

Associated factors and abnormal dorsal raphe nucleus connectivity patterns of freezing of gait in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a common, disabling symptom of Parkinson's disease (PD), and its exact pathophysiological mechanism is still poorly understood. The control of gait is a complex process that may be influenced by emotions modulated by serotonergic networks. Therefore, this study aimed to determine factors associated with FOG in PD patients and to evaluate the importance of the dorsal raphe nucleus (DRN; central node in the serotoninergic system) in FOG pathophysiology. METHODS: We combined cross-sectional survey data from 453 PD patients. According to the Freezing of Gait Questionnaire (FOGQ), patients were divided into two groups: the "PD with frozen gait (PD-FOG)" and "PD without frozen gait (PD-nFOG)" groups. Demographic characteristics, clinical features, and motor and nonmotor symptoms (NMS) assessments of PD patients were recorded. Univariate statistical analysis was performed between the two groups, and then regression analysis was performed on related factors. We also acquired resting-state functional MRI (rs-fMRI) data from 20 PD-FOG, 21 PD-nFOG, and 22 healthy controls (HCs) who were randomly chosen. We defined seeds in the DRN to evaluate functional connectivity (FC) patterns. RESULTS: The overall frequency of FOG was 11.9% patients in the PD-FOG group were older, had a longer disease duration, had a higher levodopa equivalent daily dose, had more severe motor symptoms and worse quality of life, had a higher proportion of dyskinesia, wearing-off and postural instability/gait difficulty (PIGD) clinical phenotype, and experienced more depression and impaired sleep function than those in the PD-nFOG group. Logistic regression analysis showed that H&Ystage ≥ 3, UPDRS-III scores, PIGD clinical phenotype and excessive daytime sleepiness were associated with FOG. In addition, there was significantly lower FC between the DRN and some cortical structures, including the supplementary motor area (SMA), left superior frontal gyrus (SFG), and left median cingulated cortex (MCC) in PD-FOG patients than HCs and PD-nFOG patients. CONCLUSIONS: These results demonstrate that the severity of PD and PIGD clinical phenotype are associated factors for freezing and that DRN dysfunction may play a key role in PD-related NMS and FOG. An abnormal cortical and brainstem networks may contribute to the mechanisms underlying FOG.

Preliminary Findings on Proline-Rich Protein 14 as a Diagnostic Biomarker for Parkinson's Disease.

The nuclear envelope component proline-rich protein 14 (PRR14) is involved in the nuclear morphological alteration and activation of the mTOR (mammalian target of rapamycin) signaling pathway, and has been repeatedly shown to be upregulated in patients with Parkinson's disease (PD). The aim of this study was to explore whether PRR14 can be used as a potential biomarker for the diagnosis of PD. We compared PRR14 expression in PD patients and normal controls in gene expression omnibus (GEO) data. Quantitative enzyme-linked immunosorbent assay (ELISA) was used to detect PRR14 expression in PD patients and age- and sex-matched controls. The relationship between serum PRR14 and clinical phenotype was evaluated using correlation analysis and logistic regression. The expression of PRR14 in whole blood, substantia nigra, and medial substantia nigra was significantly higher in PD patients than in the healthy control group. Compared to plasma, serum was more suitable for the detection of PRR14. Furthermore, serum PRR14 level in PD patients was significantly higher than that in age- and sex-matched controls. The area under the curve for serum PRR14 level in the ability to identify PD versus age- and sex-matched controls was 0.786. In addition, serum PRR14 level was found to correlate with constipation in PD patients. Our findings demonstrate for the first time that serum PRR14 is a potential biomarker for PD.

MicroRNA-409-3p Targeting at ATXN3 Reduces the Apoptosis of Dopamine Neurons Based on the Profile of miRNAs in the Cerebrospinal Fluid of Early Parkinson's Disease.

Precise recognition of early Parkinson's disease (PD) has always been a challenging task requiring more feasible biomarkers to be integrated to improve diagnostic accuracy. MicroRNAs (miRNAs) of cerebrospinal fluid (CSF) are believed to be potential and promising candidate biomarkers for PD. However, the role of altered miRNAs of CSF play in PD is unclear. Here, we recruited patients with early stages of PD and controls to analyze the expression of miRNA in CSF by the Next Generation Sequencing (NGS). Furthermore, we tested the levels of these miRNA in SH-SY5Y cells treated with MPP+ using real-time quantitative PCR. We found 21 miRNAs were upregulated in CSF of early PD patients and miR-409-3p, one of the identified 21 miRNAs, was further confirmed in SH-SY5Y cells treated with MPP+. Also, more cells survived in the overexpression of the miR-409-3p group when SH-SY5Y cells and mice were treated with MPP+ and MPTP, respectively. Mechanistically, we demonstrated the binding of miR-409-3p and 3'UTR of ATXN3 through a dual luciferase reporter gene assay. Moreover, miR-409-3p mimic reduced the aggregation of polyglutamine-expanded mutant of ATXN3 and apoptosis. Our results provide experimental evidence for miR-409-3p in CSF as a diagnostic marker of PD.

Assessing the Effects of Vitamin D on Neural Network Function in Patients With Parkinson's Disease by Measuring the Fraction Amplitude of Low-Frequency Fluctuation.

Background: Recently, many studies have shown that low vitamin D (VD) levels may be related to an increased risk of Parkinson's disease (PD), but the underlying mechanisms remain unclear. Objective: To explore the relationship between PD and VD levels, as well as to analyze the effects of VD on spontaneous brain activity and explore the possible mechanism of its involvement in PD risk. Methods: In a cross-sectional study, we quantified the difference in VD levels between 330 PD patients and 209 healthy controls (HC) to explore the correlation between VD and PD risk. We also acquired resting-state Functional Magnetic Resonance Imaging (rs-fMRI) data from 46 PD patients and 21 HC. The PD patients were divided into three groups according to 25(OH)D levels: PD patients with VD deficiency (PD + VDD), PD patients with VD insufficiency (PD + VDI), and PD patients with normal VD (PD + NVD). The effect of VD status on spontaneous neuronal activity in the whole brain was analyzed by measuring the fraction amplitude of low-frequency fluctuation (fALFF). Results: Compared with HC, the PD patients had lower serum 25(OH)D levels (23.60 ± 7.27 vs. 25.60 ± 5.78, P < 0.001). The 25(OH)D level may have a potential dose-dependent effect on the risk of PD (P trend = 0.007). A high risk of PD was associated with VD deficiency [25(OH)D < 20 ng/mL, OR = 2.319], and the lowest quartile of 25(OH)D concentration was associated with a high risk of PD (OR = 1.941). In the rs-fMRI study, PD + VDD patients had wider brain regions with altered fALFF than other PD groups when compared with the corresponding HC groups. Both PD + VDD and PD + VDI showed higher fALFF in the cuneus, left precuneus, calcarine cortex and right lingual, as well as lower fALFF in the left middle temporal gyrus. PD + VDD patients also showed higher fALFF in the left superior, middle and inferior frontal gyri, as well as the left precentral gyrus than HC. Among PD patients, there was only a statistically significant difference in fALFF between the PD + VDD and PD + NVD groups. Compared with the PD + NVD group, PD + VDD patients exhibited higher fALFF in the left precentral and left postcentral gyrus, as well as the left inferior parietal lobule. Conclusion: These results demonstrate that PD patients had lower serum VD levels than HC, and VD may have a potential dose-dependent effect on PD risk. Lower serum VD levels can affect the spontaneous neuronal activity of default-mode network (DMN) and visual pathway neurons in PD patients, providing a possible mechanism for its effect on PD risk.

The PARK2 Mutation Associated with Parkinson's Disease Enhances the Vulnerability of Peripheral Blood Lymphocytes to Paraquat.

Parkinson's disease (PD) is the second most common neurodegenerative disease in middle-aged and elderly people. However, the etiology and pathogenesis of PD are still unclear and there is a lack of reliable biomarkers for early molecular diagnosis. Parkin (encoded by PARK2) is a ubiquitin E3 ligase that participates in mitochondrial homeostasis, the ubiquitin-proteasome pathway, oxidative stress response, and cell death pathways, which are involved in the pathogenesis of PD. However, Parkin is also expressed in peripheral blood lymphocytes (PBLs). In this study, permanent lymphocyte lines were established from the peripheral blood of sporadic PD (sPD) patients, PARK2 mutation carriers, and healthy controls. Reactive oxygen species (ROS), function of the mitochondrial respiratory chain complex I, and apoptosis were analyzed in the PBLs. There was no significant difference in ROS, mitochondrial respiratory chain complex I, and apoptosis between the experimental groups and the control group without paraquat treatment. Compared with the control group of healthy subjects, we found an increase of ROS (control 100 ± 0, sPD 275.53 ± 79.11, and C441R 340 ± 99.67) and apoptosis, as well as a decline in the function of mitochondrial respiratory chain complex I in PBLs of PARK2 mutation carriers and sPD after the treatment of paraquat (control 0.65 ± 0.08, sPD 0.44 ± 0.08, and C441R 0.32 ± 0.08). Moreover, overexpression of the wild-type (WT) PARK2 in HeLa cells and immortalized PBLs could rescue mitochondrial function and partially inhibit apoptosis following paraquat treatment, while the C441R mutation could not. Thus, ROS levels, activity of mitochondrial respiratory chain complex I, and apoptosis of PBLs are potential diagnostic biomarkers of PD.

The relationships of vitamin D, vitamin D receptor gene polymorphisms, and vitamin D supplementation with Parkinson's disease.

In recent years, many studies have investigated the correlations between Parkinson's disease (PD) and vitamin D status, but the conclusion remains elusive. The present review focuses on the associations between PD and serum vitamin D levels by reviewing studies on the associations of PD with serum vitamin D levels and vitamin D receptor (VDR) gene polymorphisms from PubMed, Web of Science, Cochrane Library, and Embase databases. We found that PD patients have lower vitamin D levels than healthy controls and that the vitamin D concentrations are negatively correlated with PD risk and severity. Furthermore, higher vitamin D concentrations are linked to better cognitive function and mood in PD patients. Findings on the relationship between VDR gene polymorphisms and the risk of PD are inconsistent, but the FokI (C/T) polymorphism is significantly linked with PD. The occurrence of FokI (C/T) gene polymorphism may influence the risk, severity, and cognitive ability of PD patients, while also possibly influencing the effect of Vitamin D3 supplementation in PD patients. In view of the neuroprotective effects of vitamin D and the close association between vitamin D and dopaminergic neurotransmission, interventional prospective studies on vitamin D supplementation in PD patients should be conducted in the future.