Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity.

DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that the PD-associated protein DJ-1 plays an essential role in modulating DNA double-strand break (DSB) repair. Specifically, DJ-1 is a DNA damage response (DDR) protein that can be recruited to DNA damage sites, where it promotes DSB repair through both homologous recombination and nonhomologous end joining. Mechanistically, DJ-1 interacts directly with PARP1, a nuclear enzyme essential for genomic stability, and stimulates its enzymatic activity during DNA repair. Importantly, cells from PD patients with the DJ-1 mutation also have defective PARP1 activity and impaired repair of DSBs. In summary, our findings uncover a novel function of nuclear DJ-1 in DNA repair and genome stability maintenance, and suggest that defective DNA repair may contribute to the pathogenesis of PD linked to DJ-1 mutations.

DNA Damage-Mediated Neurotoxicity in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease around the world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in the pathophysiology of PD. There is growing evidence suggesting that DNA damage is involved in the propagation of cellular damage in PD, leading to neuropathology under different conditions. Here, we reviewed the current work on DNA damage repair in PD. First, we outlined the evidence and causes of DNA damage in PD. Second, we described the potential pathways by which DNA damage mediates neurotoxicity in PD and discussed the precise mechanisms that drive these processes by DNA damage. In addition, we looked ahead to the potential interventions targeting DNA damage and repair. Finally, based on the current status of research, key problems that need to be addressed in future research were proposed.

Association of Concurrent Olfactory Dysfunction and Probable Rapid Eye Movement Sleep Behavior Disorder with Early Parkinson's Disease Progression.

Background: Parkinson's disease (PD), with either rapid eye movement sleep behavior disorder (RBD) or olfactory dysfunction (OD), has been associated with disease progression. However, there is currently heterogeneity in predicting prognosis. Objectives: To identify whether the concurrent presence of OD and probable RBD (pRBD) in PD (Dual hit in PD, PD-DH) is associated with disease progression. Methods: We included 420 patients with de novo PD from the Parkinson's Progression Markers Initiative: 180 PD only (PD), 82 PD with OD (PD-OD), 94 PD with pRBD (PD-pRBD), and 64 PD with both OD and pRBD (PD-DH). Participants underwent motor and nonmotor evaluations, dopamine transporter imaging, and cerebrospinal fluid (CSF) assessment. Data were analyzed with generalized estimating equations and Cox proportional hazards analysis. Results: The PD-DH subtype was associated with higher scores and faster progression rates in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Parts II and III. Also, patients in PD-DH group had faster deterioration in nonmotor symptoms, including MDS-UPDRS Part I score, Montreal Cognitive Assessment, Hopkins Verbal Learning Test-Revised, Wechsler Memory Scale-Third edition (WMS-III) Letter Number Sequencing score, Symbol Digit Modalities Test, and Scales for Outcomes in PD-Autonomic scores, with all P values <0.002. Moreover, the PD-DH subtype had a higher mild cognitive impairment risk (hazard ratio = 1.756, 95% confidence interval [CI] = 1.132-2.722; P = 0.012), faster decline in caudate standard uptake values (ß = -0.03, 95% CI = -0.06 to -0.008, P = 0.012), and CSF α-synuclein levels (ß = -77, 95% CI = -149 to -5, P = 0.034) than the PD group. Conclusion: Coexisting pRBD and OD in patients with PD may be associated with faster progressions in motor measurements and in cognitive and autonomic symptoms, indicating PD-DH as a more aggressive subtype for PD.

Decoding the Role of Familial Parkinson's Disease-Related Genes in DNA Damage and Repair.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of midbrain substantia nigra pars compacta dopaminergic neurons and the formation of Lewy bodies. Over the years, researchers have gained extensive knowledge about dopaminergic neuron degeneration from the perspective of the environmental and disease-causing genetic factors; however, there is still no disease-modifying therapy. Aging has long been recognized as a major risk factor for PD; however, little is known about how aging contributes to the disease development. Genome instability is the main driving force behind aging, and has been poorly studied in patients with PD. Here, we summarize the evidence for nuclear DNA damage in PD. We also discuss the molecular mechanisms of nuclear DNA damage and repair in PD, especially from the perspective of familial PD-related mutant genes. Understanding the significance of DNA damage and repair may provide new potential intervention targets for treating PD.

Quercetin Protects against MPP+/MPTP-Induced Dopaminergic Neuron Death in Parkinson's Disease by Inhibiting Ferroptosis.

Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death of dopaminergic neurons in substantia nigra compacta (SNc) of Parkinson's disease (PD) patients. Quercetin (QCT), a natural flavonoid, has multiple pharmacological activities. However, it has not been established whether QCT can protect against dopaminergic neuron death by inhibiting ferroptosis. In this study, we investigated the potential antiferroptotic effects of QCT in cellular models established using specific ferroptosis inducers (Erastin and RSL-3) and MPP+. The effects were also explored using MPTP-induced PD mouse models. The cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Variations in mitochondrial morphology were evaluated by transmission electron microscopy (TEM) while the mitochondrial membrane potential, mass, and ROS were measured by fluorescent probes. Lipid peroxidation levels were assayed through measurement of lipid ROS, MDA, GSH, and SOD levels. The effects of QCT on MPTP-induced behavioral disorders were examined by rotarod and open field tests. In vitro and in vivo, QCT significantly inhibited ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Additionally, QCT ameliorated motor behavioral impairments and protected against the loss of dopaminergic neurons in MPTP-induced PD models. Interestingly, Nrf2 knockdown alleviated the protective effects of QCT against ferroptosis. In conclusion, these results demonstrate that ferroptosis is involved in MPP+/MPTP-induced PD, and QCT inhibits ferroptosis by activating the Nrf2 protein. Therefore, QCT is a potential agent for preventing the loss of dopaminergic neurons by targeting ferroptosis.

Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease.

BACKGROUND: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α-synuclein pathology. OBJECTIVE: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD). METHODS: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow-up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4. RESULTS: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (ß = 0.283, P = 0.026, 95% confidence interval: 0.033-0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid ß burden (ß = 0.761, P < 0.001, 95% confidence interval: 0.0356-1.167). CONCLUSIONS: APOE ε4 may be associated with rapid motor progression in PD. © 2021 International Parkinson and Movement Disorder Society.

[Comparison of soil organic matter, bulk density and clay content in small watersheds under different ecological managements of Loess Plateau, China]. / 黄土高原不同生态治理小流域土壤有机质、容重及黏粒含量的对比.

To explore the effects of small watersheds with different ecological managements on soil properties, the spatial differences of soil organic matter (SOM), bulk density (BD), and clay content (CC) in the four facets, including slope aspect, slope position, zone, and soil layer, were analyzed between Yangjiagou (YJG, artificial Robinia pseudoacacia forest watershed) and Dongzhuanggou (DZG, closed grassland watershed). The results showed that SOM, BD and CC were 12.78 g·kg-1, 1.24 g·cm-3, 19.2% for YJG and 11.13 g·kg-1, 1.21 g·cm-3, 18.2% for DZG, respectively. The values for YJG were slightly higher than those for DZG, but the difference was insignificant. All indices in the east slope were bigger than those in the west slope. Across different slope positions, the variation of BD was small, SOM and CC showed increasing trends from top to bottom. BD and CC declined downward the watershed, whereas SOM changed in an opposite trend. From the soil surface down to 60 cm soil depth, BD and CC increased and SOM decreased. The spatial sensitivity followed CC > SOM > BD, and the effects of the spatial factors can be ordered as soil layer > zone > slope aspect > slope position. There were significant differences in CC of the upper reaches, BD and CC of the middle reaches between the two basins. The sensitivity of each index to slope position, zone and soil layer in YJG was lower than that in DZG.

Myocardial protection technique for off-pump coronary artery bypass grafting combined with valve surgery / 局解手术学杂志

Objective To investigate the application of myocardial protection technique in off-pump coronary artery bypass grafting (CABG) combined with valve surgery.Methods Forty-five patients who received CABG combined valve surgery in the cardiothoracic surgery department of our hospital from February 2015 to March 2017 were as the research object.All of the patients were treated by myocardial protection technique in off-pump CABG combined with valve surgery.The preoperative and postoperative heart function rating and color ultra results and surgical patients discharged to evaluate the method.Results There was no difference in left ventricular ejection fraction before and after surgery(P ＞ 0.05).left ventricular end diastolic diameter and left atrial end diastolic diameter at 7 days after operation was significantly lower than those before operation,the differences were significant (P ＜ 0.05).After followed up for 3 months,the level Ⅰ and level Ⅱof cardiac function increased significantly in 29 cases,heart function classification(NYHA) after 3 months was significantly better than that before the surgery,the difference was significant(P ＜ 0.05).Mediastinal infection occurred in 1 case and poor healing of wound in 1 case,healing after active treatment.Conclusion Myocardial protection technique in off-pump CABG combined with valve surgery plays an important role in the whole surgical process and ensures the operation effect.

[Runoff and sediment yielding processes on red soil engineering accumulation containing gravels by a simulated rainfall experiment].

Engineering accumulation formed in production and construction projects is characterized by unique structure and complex material composition. Characteristics of soil erosion on the engineering accumulation significantly differ from those on farmland. An artificially simulated rainfall experiment was carried out to investigate the effects of rainfall intensity on the processes of runoff and sediment yielding on the engineering accumulation of different gravel contents (0%, 10%, 20% and 30%) in red soil regions. Results showed that the initial time of runoff generation decreased with increases in rainfall intensity and gravel content, the decreased amplitudes being about 48.5%-77.9% and 4.2%-34.2%, respectively. The initial time was found to be a power function of rainfall intensity. Both runoff velocity and runoff rate manifested a trend of first rising and then in a steady state with runoff duration. Rainfall intensity was found to be the main factor influencing runoff velocity and runoff rate, whereas the influence of gravel content was not significant. About 10% of gravel content was determined to be a critical value in the influence of gravel content on runoff volume. For the underlying surface of 10% gravel content, the runoff volume was least at rainfall intensity of 1.0 mm · min(-1) and maximum at rainfall intensity of greater than 1.0 mm · min(-1). The runoff volume in- creased 10%-60% with increase in rainfall intensity. Sediment concentration showed a sharp decline in first 6 min and then in a stable state in rest of time. Influence of rainfall intensity on sediment concentration decreased as gravel content increased. Gravels could reduce sediment yield significantly at rainfall intensity of greater than 1.0 mm · min(-1). Sediment yield was found to be a linear function of rainfall intensity and gravel content.

Distribution and location of Daxx in cervical epithelial cells with high risk human papillomavirus positive.

AIMS: To provide the basis for further exploring the effect and its mechanism of Death domain associated protein (Daxx) on the progress of cervical carcinoma induced by human papillomavirus (HPV), the distribution and location of Daxx in cervical carcinoma with high risk HPV(HR-HPV) positive was analyzed. METHODS: The samples of normal cervical epithelial cells, cervical intraepithelial neoplasia grade I (CINI), CINII CINIII and cervical cancers were collected. Immunohistochemistry assay was used to analyze the distributions and locations of Daxx in the cervical tissue. Indirect immunoinfluorescence test was utilized to observe the locations of Daxx in Caski cells with HPV16 positive. RESULTS: Under the light microscopy, the brown signals of Daxx distributed in the nuclei of normal cervical epithelial cells; Daxx mainly distributed in nuclear membrane and there were a small amount of Daxx in the nuclei in CINI. Daxx intensively distributed in the cytoplasm and cell membrane in CINII, CINIII and cervical cancer. Under fluorescent microscopy, the distribution and location of Daxx in Caski cells was similarly to that in cervical cells of CINII, CINIII and cervical cancer. CONCLUSION: In the progress of the cervical cancer, Daxx gradually translocates from nucleus into nuclear membrane, cytoplasm and cell membrane. Daxx locates in the cytoplasm and cell membrane in CINII, CINIII and cervical cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/4671548951113870.