LRRK2 interacts with ATM and regulates Mdm2-p53 cell proliferation axis in response to genotoxic stress.

Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unknown. DNA damage causes cancer, and DNA damage responses are among the most important pathways in cancer biology. To understand the role of LRRK2 in DNA damage response pathway, we induced DNA damage by applying genotoxic stress to the cells with Adriamycin. We found that DNA damage enhances LRRK2 phosphorylation at Serine 910, Serine 935 and Serine 1292. We further showed that LRRK2 phosphorylation is abolished in the absence of ATM, suggesting that LRRK2 phosphorylation requires ATM. It should also be noted that LRRK2 interacts with ATM. In contrast, overexpression or knockdown of LRRK2 does not affect ATM phosphorylation, indicating that LRRK2 is the downstream target of ATM in response to DNA damage. Moreover, we demonstrated that LRRK2 increases the expression of p53 and p21 by increasing the Mdm2 phosphorylation in response to DNA damage. Loss-of-function in LRRK2 has the opposite effect to that of LRRK2. In addition, FACS analysis revealed that LRRK2 enhances cell cycle progression into S phase in response to DNA damage, a finding that was confirmed by 5-bromo-2'-deoxyuridine immunostaining. Taken together, our findings demonstrate that LRRK2 plays an important role in the ATM-Mdm2-p53 pathway that regulates cell proliferation in response to DNA damage.

miR-27b shapes the presynaptic transcriptome and influences neurotransmission by silencing the polycomb group protein Bmi1.

BACKGROUND: MicroRNAs (miRNAs) are short non-coding RNAs that are emerging as important post-transcriptional regulators of neuronal and synaptic development. The precise impact of miRNAs on presynaptic function and neurotransmission remains, however, poorly understood. RESULTS: Here, we identify miR-27b-an abundant neuronal miRNA implicated in neurological disorders-as a global regulator of the presynaptic transcriptome. miR-27b influences the expression of three quarters of genes associated with presynaptic function in cortical neurons. Contrary to expectation, a large majority of these genes are up-regulated by miR-27b. This stimulatory effect is mediated by miR-27b-directed silencing of several transcriptional repressors that cooperate to suppress the presynaptic transcriptome. The strongest repressive activity appears to be mediated by Bmi1, a component of the polycomb repressive complex implicated in self-renewal of neural stem cells. miR-27b knockdown leads to reduced synaptogenesis and to a marked decrease in neural network activity, which is fully restored by RNAi-mediated silencing of Bmi1. CONCLUSIONS: We conclude that silencing of Bmi1 by miR-27b relieves repression of the presynaptic transcriptome and supports neurotransmission in cortical networks. These results expand the repressive activity of Bmi1 to genes involved in synaptic function and identify a unique post-transcriptional circuitry that stimulates expression of synaptic genes and promotes synapse differentiation.

[Food-borne Parasitic Infection in Intermediate Hosts in Ninghai County of Zhejiang Province].

To understand the status of food-borne parasitic infection in intermediate hosts in Ninghai County of Zhejiang Province, freshwater crabs were collected from 4 towns of the County to detect the infection with metacercariae of Paragonimus, and frogs were collected from 8 towns to examine the infection with plerocercoid of Spirometra mansoni from May to September, 2015. Among the 339 freshwater crabs collected, the infection rate was 9.1%（31/339）, with each crab containing 6.7 metacercariae of Paragonimus on average. Among the 348 frogs collected, the infection rate was 11.5%（40/348）, with each frog containing 2.2 plerocercoids on average. In conclusion, there is a high rate of food-borne parasitic infection in intermediate hosts in Ninghai County. Comprehensive prevention and control measures are needed.

Aquaporin-4 mediates astrocyte response to ß-amyloid.

It has been demonstrated that the water channel protein aquaporin-4 (AQP4) plays an important role in astrocyte plasticity in response to a variety of injuries or stimuli. However, the potential role of AQP4 in astrocyte response to ß-amyloid (Aß) has not been studied. The purpose of this study was to investigate this issue. Compared to media control, the lower concentrations of Aß(1-42) (0.1-1 µM) increased AQP4 expression in cultured mouse cortical astrocytes, while the higher concentrations of Aß(1-42) (10 µM) decreased AQP4 expression. AQP4 gene knockout reduced Aß(1-42)-induced astrocyte activation and apoptosis, which was associated with a reduction in the uptake of Aß via decreased upregulation of low-density lipoprotein receptor related protein-1. Moreover, time-course and levels of Aß(1-42)-induced mitogen-activated protein kinase phosphorylation were altered in AQP4 null astrocytes compared with wild-type controls. Our data reveal a novel role of AQP4 in the uptake of Aß by astrocytes, indicating that AQP4 is a molecular target for Alzheimer's disease.

Dietary Patterns Are Associated With Multi-Dimensional Cognitive Functions Among Adults Aged 55 and Older in China.

BACKGROUND: The intake of certain food and nutrients may play a crucial role in cognitive health. However, research on the relationship between dietary patterns and cognitive function is limited. This study aims to investigate the associations between dietary patterns and multi-dimensional cognitive functions, such as global cognitive status and related domain profiles, mild cognitive impairment (MCI), and four major subtypes of Chinese adults. METHODS: Using the baseline data from the Community-based Cohort Study on Nervous System Diseases (2018-2019), we selected 4,309 Chinese adults aged 55 years and older as subjects with complete diet, cognition, and other related data. We collected food data for the past 12 months with a valid semi-quantitative food frequency questionnaire. Diving 49 food items into 13 subgroups, we used factor analysis to derive the main dietary patterns. We evaluated cognitive functions based on the scores of the Montreal Cognitive Assessment (MoCA) and used quantile regression and multivariable logistic regression to examine the relationship between dietary patterns and cognitive-related outcomes. RESULTS: We identified four dietary patterns, explaining 50.11% of the total variance: "meat-preferred" pattern, "plant-preferred" pattern, "eggs- and dairy-preferred" pattern, and "grain-preferred" pattern. After adjusting for all potential confounders, the "meat-preferred" pattern and the "plant-preferred" pattern were associated with higher scores of global cognition and several cognitive domains (p <0.05), while the "grain-preferred" pattern was associated with lower scores of global cognition (ß = -0.36, p <0.05), execution (ß = -0.19, p <0.05), visuospatial (ß = -0.09, p <0.05), and language (ß = -0.05, p <0.05). Adults adhering to the "meat-preferred" pattern and the "plant-preferred" pattern had decreased odds of MCI and some MCI subtypes (p-trend <0.05); in contrast, those in the top quartiles of the "grain-preferred" pattern had increased odds of MCI [adjusted odds ratio (AOR) = 1.34, 95% CI: 1.11-1.63, p-trend = 0.003]. CONCLUSIONS: Adhering to the "plant-preferred" pattern and the "meat-preferred" pattern may help improve the multi-dimensional cognitive functions; on the contrary, adhering to the "grain-preferred" pattern may worse cognitive health. More prospective studies in this field are needed to strengthen the evidence.

[Investigation of pinworm infection among Kindergarten children in Ninghai County].

6,257 children in 39 kindergartens were examined by adhesive tape wiping in the morning during April, 2009 to November, 2010, and 460 children were found pinworm infected with a prevalence of 7.4% (460/6,257), 7.7% (260/3,359) in girls and 6.9% (200/2,898) in boys. Children in junior class had lowest infection rate of 4.6% (77/1,667), while children in senior class had highest rate of 9.7% (252/2,594) (chi2 = 36.8, P < 0.01). Furthermore, the rate in public kindergartens (6.5%, 255/3,927) was lower than that in private kindergartens (8.8%, 255/2,330) (chi2 = 11.4, P < 0.01) , and the rate in urban kindergartens (12.4%, 199/1,611) was much higher than that in rural kindergartens (5.6%, 261/4,646) (chi2 = 79.7, P < 0.01) . Evidently, pinworm prevalence is high in children in Ninghai, and it is higher in private and urban kindergartens than in public and rural ones respectively.

Heterozygous knockout of the Bmi-1 gene causes an early onset of phenotypes associated with brain aging.

Previous studies reported that the polycomb group gene Bmi-1 is downregulated in the aging brain. The aim of this study was to investigate whether decreased Bmi-1 expression accelerates brain aging by analyzing the brain phenotype of adult Bmi-1 heterozygous knockout (Bmi-1(+/-)) mice. An 8-month-old Bmi-1(+/-) brains demonstrated mild oxidative stress, revealed by significant increases in hydroxy radical and nitrotyrosine, and nonsignificant increases in reactive oxygen species and malonaldehyde compared with the wild-type littermates. Bmi-1(+/-) hippocampus had high apoptotic percentage and lipofuscin deposition in pyramidal neurons associated with upregulation of cyclin-dependent kinase inhibitors p19, p27, and p53 and downregulation of anti-apoptotic protein Bcl-2. Mild activation of astrocytes was also observed in Bmi-1(+/-) hippocampus. Furthermore, Bmi-1(+/-) mice showed mild spatial memory impairment in the Morris Water Maze test. These results demonstrate that heterozygous Bmi-1 gene knockout causes an early onset of age-related brain changes, suggesting that Bmi-1 has a role in regulating brain aging.

MicroRNAs are required for the feature maintenance and differentiation of brown adipocytes.

Brown adipose tissue (BAT) is specialized to burn lipids for heat generation as a natural defense against cold and obesity. Previous studies established microRNAs (miRNAs) as essential regulators of brown adipocyte differentiation, but whether miRNAs are required for the feature maintenance of mature brown adipocytes remains unknown. To address this question, we ablated Dgcr8, a key regulator of the miRNA biogenesis pathway, in mature brown as well as in white adipocytes. Adipose tissue-specific Dgcr8 knockout mice displayed enlarged but pale interscapular brown fat with decreased expression of genes characteristic of brown fat and were intolerant to cold exposure. Primary brown adipocyte cultures in vitro confirmed that miRNAs are required for marker gene expression in mature brown adipocytes. We also demonstrated that miRNAs are essential for the browning of subcutaneous white adipocytes in vitro and in vivo. Using this animal model, we performed miRNA expression profiling analysis and identified a set of BAT-specific miRNAs that are upregulated during brown adipocyte differentiation and enriched in brown fat compared with other organs. We identified miR-182 and miR-203 as new regulators of brown adipocyte development. Taken together, our study demonstrates an essential role of miRNAs in the maintenance as well as in the differentiation of brown adipocytes.

Cellular localization of aquaporin-1 in the human and mouse trigeminal systems.

Previous studies reported that a subpopulation of mouse and rat trigeminal neurons express water channel aquaporin-1 (AQP1). In this study we make a comparative investigation of AQP1 localization in the human and mouse trigeminal systems. Immunohistochemistry and immunofluorescence results showed that AQP1 was localized to the cytoplasm and cell membrane of some medium and small-sized trigeminal neurons. Additionally, AQP1 was found in numerous peripheral trigeminal axons of humans and mice. In the central trigeminal root and brain stem, AQP1 was specifically expressed in astrocytes of humans, but was restricted to nerve fibers within the central trigeminal root and spinal trigeminal tract and nucleus in mice. Furthermore, AQP1 positive nerve fibers were present in the mucosal and submucosal layers of human and mouse oral tissues, but not in the muscular and subcutaneous layers. Fluorogold retrograde tracing demonstrated that AQP1 positive trigeminal neurons innervate the mucosa but not skin of cheek. These results reveal there are similarities and differences in the cellular localization of AQP1 between the human and mouse trigeminal systems. Selective expression of AQP1 in the trigeminal neurons innervating the oral mucosa indicates an involvement of AQP1 in oral sensory transduction.

Bmi-1 absence causes premature brain degeneration.

Bmi-1, a polycomb transcriptional repressor, is implicated in cell cycle regulation and cell senescence. Its absence results in generalized astrogliosis and epilepsy during the postnatal development, but the underlying mechanisms are poorly understood. Here, we demonstrate the occurrence of oxidative stress in the brain of four-week-old Bmi-1 null mice. The mice showed various hallmarks of neurodegeneration including synaptic loss, axonal demyelination, reactive gliosis and brain mitochondrial damage. Moreover, astroglial glutamate transporters and glutamine synthetase decreased in the Bmi-1 null hippocampus, which might contribute to the sporadic epileptic-like seizures in these mice. These results indicate that Bmi-1 is required for maintaining endogenous antioxidant defenses in the brain, and its absence subsequently causes premature brain degeneration.