RPS23RG1 modulates tau phosphorylation and axon outgrowth through regulating p35 proteasomal degradation

Tau蛋白病（Tauopathies）是由过度磷酸化的tau蛋白聚集形成神经纤维缠结为特征的一类神经退行性疾病，包括阿尔茨海默病（Alzheimer’s disease, AD）、进行性核上性麻痹（Progressive superanuclear palsy, PSP）、额颞叶痴呆（Frontotemporal dementia, FTD）等。随着全球社会结构的老龄化，tau蛋白病患者比率迅速增加，给个人和社会带来巨大的经济及精神负担。厦门大学神经科学研究所张云武教授团队最新发现RPS23RG1（RR1）的胞内羧基端区域能够与Cdk5激酶的激活蛋白p35的氨基端相互作用，介导p35的膜定位并影响其泛素化降解，从而调控在tau蛋白异常磷酸化过程中发挥重要作用的Cdk5激酶的活性。团队研究表明RPS23RG1通过其胞内羧基端与p35相互作用，介导p35膜结合和降解，从而抑制Cdk5活性，平衡tau磷酸化水平，促进轴突生长。此外，RPS23RG1的跨膜区与腺苷酸环化酶AC相互作用，抑制GSK3-β活性，同样控制tau过度磷酸化。提示RPS23RG1是改善tau过度磷酸化水平及治疗tau蛋白病的潜在靶点。 厦门大学医学院神经科学研究所博士后赵东栋为该研究第一作者，张云武教授为通讯作者。【Abstract】Tauopathies are a group of neurodegenerative diseases characterized by hyperphosphorylation of the microtubule-binding protein, tau, and typically feature axon impairment and synaptic dysfunction. Cyclin-dependent kinase5 (Cdk5) is a major tau kinase and its activity requires p35 or p25 regulatory subunits. P35 is subjected to rapid proteasomal degradation in its membrane-bound form and is cleaved by calpain under stress to a stable p25 form, leading to aberrant Cdk5 activation and tau hyperphosphorylation. The type Ib transmembrane protein RPS23RG1 has been implicated in Alzheimer’s disease (AD). However, physiological and pathological roles for RPS23RG1 in AD and other tauopathies are largely unclear. Herein, we observed retarded axon outgrowth, elevated p35 and p25 protein levels, and increased tau phosphorylation at major Cdk5 phosphorylation sites in Rps23rg1 knockout (KO) mice. Both downregulation of p35 and the Cdk5 inhibitor roscovitine attenuated tau hyperphosphorylation and axon outgrowth impairment in Rps23rg1 KO neurons. Interestingly, interactions between the RPS23RG1 carboxyl-terminus and p35 amino-terminus promoted p35 membrane distribution and proteasomal degradation. Moreover, P301L tau transgenic (Tg) mice showed increased tau hyperphosphorylation with reduced RPS23RG1 levels and impaired axon outgrowth. Overexpression of RPS23RG1 markedly attenuated tau hyperphosphorylation and axon outgrowth defects in P301L tau Tg neurons. Our results demonstrate the involvement of RPS23RG1 in tauopathy disorders, and implicate a role for RPS23RG1 in inhibiting tau hyperphosphorylation through homeostatic p35 degradation and suppression of Cdk5 activation. Reduced RPS23RG1 levels in tauopathy trigger aberrant Cdk5-p35 activation, consequent tau hyperphosphorylation, and axon outgrowth impairment, suggesting that RPS23RG1 may be a potential therapeutic target in tauopathy disorders.This work was supported by grants from National Key Research and Development Program of China (2016YFC1305903 and 2018YFC2000400 to Y-wZ), National Natural Science Foundation of China (81771377, U1705285, 91332112, and 81225008 to Y-wZ), Fundamental Research Funds for the Central Universities (20720180049 to Y-wZ), the Fujian Provincial Health Commission-Education Department Joint Tackling Plan (WKJ2016-2-18 to F-rL), and Postdoctoral Science Foundation of China (2020M671948 to DZ)

Altered spontaneous brain activity during dobutamine challenge in healthy young adults: A resting-state functional magnetic resonance imaging study

IntroductionThere is a growing interest in exploring brain-heart interactions. However, few studies have investigated the brain-heart interactions in healthy populations, especially in healthy young adults. The aim of this study was to explore the association between cardiovascular and spontaneous brain activities during dobutamine infusion in healthy young adults.MethodsForty-eight right-handed healthy participants (43 males and 5 females, range: 22–34 years) underwent vital signs monitoring, cognitive function assessment and brain MRI scans. Cardiovascular function was evaluated using blood pressure and heart rate, while two resting-state functional magnetic resonance imaging (rs-fMRI) methods—regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF)—were used together to reflect the local neural activity of the brain. Logistic regression was used to model the association between brain and heart.ResultsResults showed that blood pressure and heart rate significantly increased after dobutamine infusion, and the performance in brain functional activity was the decrease in ReHo in the left gyrus rectus and in ALFF in the left frontal superior orbital. The results of logistic regression showed that the difference of diastolic blood pressure (DBP) had significant positive relationship with the degree of change of ReHo, while the difference of systolic blood pressure (SBP) had significant negative impact on the degree of change in ALFF.DiscussionThese findings suggest that the brain-heart interactions exist in healthy young adults under acute cardiovascular alterations, and more attention should be paid to blood pressure changes in young adults and assessment of frontal lobe function to provide them with more effective health protection management

Comparative Metaproteomic Analysis on Consecutively Rehmannia glutinosa-Monocultured Rhizosphere Soil

National Natural Science Foundation of China [30772729, 30671220, 31070403]; Natural Science Foundation of Fujian province, China [2008J0051]Background: The consecutive monoculture for most of medicinal plants, such as Rehmannia glutinosa, results in a significant reduction in the yield and quality. There is an urgent need to study for the sustainable development of Chinese herbaceous medicine. Methodology/Principal Findings: Comparative metaproteomics of rhizosphere soil was developed and used to analyze the underlying mechanism of the consecutive monoculture problems of R. glutinosa. The 2D-gel patterns of protein spots for the soil samples showed a strong matrix dependency. Among the spots, 103 spots with high resolution and repeatability were randomly selected and successfully identified by MALDI TOF-TOF MS for a rhizosphere soil metaproteomic profile analysis. These proteins originating from plants and microorganisms play important roles in nutrient cycles and energy flow in rhizospheric soil ecosystem. They function in protein, nucleotide and secondary metabolisms, signal transduction and resistance. Comparative metaproteomics analysis revealed 33 differentially expressed protein spots in rhizosphere soil in response to increasing years of monoculture. Among them, plant proteins related to carbon and nitrogen metabolism and stress response, were mostly up-regulated except a down-regulated protein (glutathione S-transferase) involving detoxification. The phenylalanine ammonia-lyase was believed to participate in the phenylpropanoid metabolism as shown with a considerable increase in total phenolic acid content with increasing years of monoculture. Microbial proteins related to protein metabolism and cell wall biosynthesis, were up-regulated except a down-regulated protein (geranylgeranyl pyrophosphate synthase) functioning in diterpenoid synthesis. The results suggest that the consecutive monoculture of R. glutinosa changes the soil microbial ecology due to the exudates accumulation, as a result, the nutrient cycles are affected, leading to the retardation of plant growth and development. Conclusions/Significance: Our results demonstrated the interactions among plant, soil and microflora in the proteomic level are crucial for the productivity and quality of R. glutinosa in consecutive monoculture system

Substituting dietary fishmeal with soybean meal isolate influences hepatic lipid metabolism and gut microbiota in spotted seabass (<em>Lateolabrax maculatus</em>)

This study was conducted to investigate the effects of partial substitution of dietary fishmeal (FM) by soy protein isolate (SPI) on lipid metabolism and gut microbiota of spotted seabass. A diet containing 30% FM formed the basal diet (FM), and two SPI diets were formulated in which 25% (SPI25) and 50% (SPI50) of FM were replaced by SPI. Each diet was fed to triplicates of fish for 56 days. The results showed that replacing dietary FM with SPI reduced triglyceride and cholesterol contents in the liver and serum, and the hepatic lipid droplets area was also decreased by dietary SPI inclusion. Furthermore, replacement of dietary FM with SPI markedly down-regulated the mRNA expression of genes involved in lipogenesis (srebpc-1c, fas, acc1, hmgcr, pparγ and chrebp) and lipolysis (atgl, hsl, pparα, and cpt1). Moreover, high-throughput sequencing analyses of gut microbiota revealed that dietary SPI inclusion dramatically decreased the Firmicutes/Bacteroidetes ratio. Overall, this study indicated that replacing 25-50% of dietary FM with SPI could reduce lipid accumulation in serum and liver of spotted seabass, which was associated with the suppressed hepatic lipogenesis and the remodeled gut microbiota

Effects of substituting dietary fish meal with soybean meal isolate on growth performance, digestive enzyme activity, and intestinal morphology of spotted seabass (<em>Lateolabrax maculatus</em>)

Soy protein isolate (SPI) is a promising plant protein source to replace fish meal (FM) in aquatic feeds. This study investigated the growth performance, digestive enzyme activity, and intestinal morphology of spotted seabass (Lateolabrax maculatus) fed diets with FM partially substituted by SPI. Three iso-nitrogenous and iso-lipidic diets were formulated to replace 0, 25, and 50% of FM with SPI, being abbreviated as FM, SPI25, and SPI50, respectively. Each diet was allocated to triplicates of fish for 8 weeks. The results indicated that the weight gain was gradually reduced with increasing dietary SPI levels, as did intestinal trypsin and lipase activities. However, these traits were not significantly decreased until 50% of FM was substituted by SPI. Furthermore, feed intake and lipid digestibility significantly decreased with dietary SPI inclusion. Moreover, replacing 50% of dietary FM with SPI significantly reduced the intestinal villus height and perimeter ratio, whereas these traits did not markedly differ between FM and SPI25 groups. In conclusion, this study indicated that up to 25% of dietary FM could be substituted with SPI without significantly affecting the growth, digestive enzyme activity, or intestinal morphology in spotted seabass

Mechanical vibration may be a novel adjuvant approach to promoting stability and retention following orthodontic treatment

Introduction: Orthodontic tooth movement occurs as a consequence of paradental tissue remodeling in response to applied mechanical forces. Retention is a necessary procedure to prevent relapse when orthodontic appliances are removed. Developing new methods to promote stability and retention following orthodontic treatment has always been desired. Recent studies have demonstrated the favorable effects of low magnitude, high frequency (LMHF) mechanical vibration on bone homeostasis through an ability to stimulate cell metabolism and to enhance osteoblast proliferation, osteoblastic gene expression and bone formation. The Hypothesis: In this paper, we propose that LMHF mechanical vibration is a viable adjuvant method to accelerate bone and periodontal tissue remodeling, thereby promoting stability and shortening retention time. Evaluation of the Hypothesis: Much effort has been made to explore therapies to prevent relapse and shorten orthodontic retention time with limited success. LMHF mechanical vibration may be a promising approach to accelerate alveolar bone remodeling, ultimately promote stability and shorten retention time

TAGET: A toolkit for analyzing full-length transcripts from long-read sequencing

&lt;p&gt;Polished transcripts&nbsp;of COLO829 from the PacBio platform. The original web link:&nbsp;https://downloads-ap.pacbcloud.com/public/dataset/Melanoma2019_IsoSeq/PolishedMappedTranscripts/before-SQANTI2filter/.&lt;/p&gt

PRDX6 regulates the H2O2 and blue light-induced APRE-19 cell apoptosis via down-regulating and interacting with RARA

Hereditary retinal disease (HRD) is the primary retinal degeneration that leads to severe visual impairments and refractory blindness, and the therapy of HRD was most important in ophthalmology. The apoptosis of retinal cells plays important roles in HRD progression. Therefore, in this study, we explore the mechanism of H2O2 and blue light-induced apoptosis of ARPE-19 cells. Co-immunoprecipitation (Co-IP) is employed to test the interactions between proteins, and western blotting is used to detect the protein levels. Apoptosis is analyzed by Flow cytometry. Our results found that PRDX6 could interact with RARA in ARPE-19 cells, and H2O2 and blue light could significantly reduce the RARA protein expression, and also could inhibit the interaction between PRDX6 and RARA. Using a rescue experiment, we further elucidated that H2O2 and blue light reduced the RARA expression via down-regulating PRDX6. And H2O2 and blue light induced the ARPE-19 cell apoptosis via decreasing the expression of PRDX6. Our results suggested that the interaction between PRDX6 and RARA played important roles in the apoptosis of ARPE-19 cells