CDK5-dependent BAG3 degradation modulates synaptic protein turnover

阿尔茨海默病（AD）是严重威胁人类健康的重大神经系统疾病，AD的发生发展与衰老密切相关，目前临床治疗方法十分有限。因此迫切需要从AD致病早期入手，发现和鉴定导致AD神经功能紊乱的机制和靶点，为AD的早期防治提供基础。张杰教授及其团队从高通量磷酸化蛋白质组学入手，系统研究了CDK5在神经细胞中的磷酸化底物，鉴定出了在蛋白质量控制中发挥重要功能的BAG3蛋白是CDK5的全新底物。课题组从磷酸化蛋白质组学入手，发现和阐明了细胞周期蛋白激酶5（CDK5）通过调控BAG3在维持突触蛋白水平调控中的作用机制，及其在阿尔茨海默病（AD）发生发展中的机理。 该研究是多个团队历时8年合作完成的，香港中文大学的周熙文教授、美国匹兹堡大学的Karl Herrup教授、美国Sanford-Burnham研究所的许华曦教授、美国梅奥医学中心的卜国军教授，厦门大学医学院的文磊教授、张云武教授、赵颖俊教授、薛茂强教授，军事医学科学院的袁增强教授等都参与了该工作。 厦门大学医学院2012级博士生周杰超等为文章的第一作者，张杰教授为通讯作者。Background Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer’s disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were re-examined in search for candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. Methods Quantitative phospho-proteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays were used to investigate the associated regulatory signaling networks. Histological, electrochemical and behavioral assays were performed in conditional knockout, shRNA-mediated knockdown and AD-related mice models to evaluate its relevance to synaptic homeostasis and functions. Results Among candidates with known implications in synaptic modulations, BCL2-associated athanogene-3 (BAG3) ranked the highest. CDK5-mediated phosphorylation on Ser297/Ser291 (Mouse/Human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related-mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such were reversed by ectopic BAG3 re-expression. Conclusions Our results highlight that neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.This work was supported by the National Science Foundation in China (Grant: 31571055, 81522016, 81271421 to J.Z.; 81801337 to L.L; 81774377 and 81373999 to L.W.); Fundamental Research Funds for the Central Universities of China-Xiamen University (Grant: 20720150062, 20720180049 and 20720160075 to J.Z.); Fundamental Research Funds for Fujian Province University Leading Talents (Grant JAT170003 to L.L); Hong Kong Research Grants Council (HKUST12/CRF/13G, GRF660813, GRF16101315, AoE/M-05/12 to K.H.; GRF16103317, GRF16100718 and GRF16100219 to H.-M,C.); Offices of Provost, VPRG and Dean of Science, HKUST (VPRGO12SC02 to K.H.); Chinese University of Hong Kong (CUHK) Improvement on Competitiveness in Hiring New Faculty Funding Scheme (Ref. 133), CUHK Faculty Startup Fund and Alzheimer’s Association Research Fellowship (AARF-17-531566) to H.-M, C. 该研究受到了国家自然科学基金、厦门大学校长基金、福建省卫生教育联合攻关基金等的资助

Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation

厦门大学医学院、神经科学研究所张杰教授团队发现了抑郁症新的致病基因MEN1，并阐明了MEN1调控星形胶质细胞炎症导致抑郁发生发展的新机制，为抑郁症的诊治提供了新靶点和方向。抑郁症是严重威胁人类健康的重大神经系统疾病，危及全球30%的人口。但对其发病机制并不清楚。张杰教授团队发现，在慢性不可预测以及LPS处理的模拟抑郁小鼠模型中，多发性内分泌肿瘤蛋白(menin)在大脑中的表达显著降低，并且在星形胶质细胞中降低最明显。为了研究menin是否参与了小鼠抑郁表型的产生，研究团队制作了多种神经系统menin条件性敲除小鼠。通过对这些小鼠行为学的检测，锁定了只有在星形胶质细胞中敲除menin后，小鼠才会表现出抑郁样表型。证实了menin可能是通过调控星形胶质细胞的功能促进了抑郁的发生。 MEN1基因的突变会导致多发性内分泌肿瘤，而内分泌的紊乱和抑郁等精神疾病有着密切的联系。下丘脑-垂体-肾上腺轴（HPA轴）的功能紊乱直接参与了抑郁的产生。基于此研究团队推测MEN1的基因突变是否也会导致抑郁的发生。通过和中国医学科学院基础所的许琪教授合作，研究团队对1000多例重度抑郁患者和800多例对照人群进行了MEN1基因的外显子测序。通过测序发现MEN1的一个SNP s375804228和抑郁的发生有着显著关联。该SNP导致menin第503位的氨基酸由G突变成D。通过功能研究进一步证实该突变可以阻断menin和p65的结合，从而过度激活NF-κB-IL-1β通路，导致神经炎症的发生。 张杰，厦门大学特聘教授、博士生导师。国家优秀青年科学基金；教育部新世纪优秀人才；福建省杰出青年科学基金；厦门市五四青年奖章等获得者。2011年8月加入厦门大学医学院神经科学研究所担任教授至今。张杰博士主要从事重大神经系统疾病（老年痴呆、帕金森、抑郁症、自闭症、术后认知障碍、胶质瘤）等的发病机制和药物开发研究。至今以第一作者或者通讯作者在国际知名期刊发表研究论文21篇。其中回国独立开展研究工作以后，作为通讯作者在 Neuron，Cell Reports, PNAS, The Journal of Neuroscience, Clinical Cancer Research，Cell Death and Disease, JBC, Chemistry，Chem. Biol. Drug Des.等杂志上发表多篇研究论文。【Abstract】Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.We thank Prof. Guanghui Jin (Xiamen University) and Prof. Xianxin Hua (University of Pennsylvania) for providing the Men1-floxp mice. This work was supported by the National Natural Science Foundation of China (grants 81522016, 81271421, and 31571055 to J.Z.; 81625008 and 31430048 to Q.X.; 81630026 to Z.Y.; 81771163 and U1405222 to H.X.; U1505227 to G.B.; 81472725 to W.M.), the Natural Science Foundation of Fujian Province of China (grant 2013J01147 and 2014J06019 to J.Z.), the Fundamental Research Funds for the Central Universities (grants 20720150062 and 20720180049 to J.Z.), the National Key Research and Development Program of China (2016YFC1305903), and CAMS Innovation Fund for Medical Sciences (grant 2016I2M1004 to Q.X.).研究工作得到国家自然科学基金项目（81522016、81271421、31571055）以及厦门大学校长基金等资助

大学生就业影响因素的实证研究

随着高校的扩招和金融危机,大学生就业问题更加严峻。本研究采用职场研究专家BillCaplin的研究成果为基础,采用问卷的形式调查了用人单位和大学生对影响就业的29项因素的理解,发现两者对23项就业影响因素的重要程度的认知有明显的差异,存在着信息不对称的情况。对就业而言,大学生唯一可控的因素就是自身的态度和能力。根据调研结果,文章有针对性地给大学生提供一些切实可行的建议。江苏省教育厅大学生实践创新计划项目阶段性成果,项目名称:江苏省高等学校大学生实践创新训练计划,项目基金编号:S200701

长期玉米连作下黑土各组分有机质化学结构特征

【目的】研究玉米连作24年前后黑土有机质红外光谱特征,探明长期玉米连作对黑土各团聚体及密度组分中有机质结构的影响,完善长期连作下土壤有机质化学结构动态变化理论。【方法】以中国科学院海伦农业生态试验站长期定位试验为研究平台,选取24年玉米连作下耕层(0—20 cm)土壤为研究对象,以试验设置前土样为对照,根据团聚体和密度大小,将土壤有机质进行分级,分别用元素分析仪和傅里叶红外光谱仪测定原土、各粒级团聚体及密度组分中的碳含量和有机质的红外光谱,对比分析玉米连作24年前后土壤有机质含量及红外光谱特征。【结果】玉米连作24年后,全土中碳含量降低5.3%,2—0.25 mm团聚体中碳含量显著降低,其他粒级团聚体中有降低的趋势;LF(游离态轻组)中碳含量增加32.74%,OF(闭蓄态轻组)中减少16.72%,MF(矿质结合态组分)中没有显著变化。土壤有机质中脂肪族-CH、多糖C-O、酚醇-OH吸收峰相对强度增强,芳香族C=C和羧基C=O吸收峰相对强度降低,脂肪族-CH/芳香族C=C比值增加。在各粒级团聚体中,-CH/C=C比值增加主要表现在>2 mm团聚体中,主成分分析也表明>2 mm团聚体中有机质结构变化最大,该粒级团聚体中3个密度组分LF、OF和MF有机质-CH/C=C比值增加,且LF中增加程度最大;在其他粒级中的3个密度组分有机质-CH/C=C比值有增加的趋势。【结论】长期玉米连作,黑土大粒级团聚体和各密度组分中有机质结构趋于脂肪化、简单化,团聚体和矿物质结合对有机质的保护作用降低,黑土有机质稳定性下降

不同水肥条件对农田土壤细菌生理菌群的影响

采用田间试验研究了大豆苗期、花期和鼓粒期在干旱、自然和充足三种水分及无肥、无机肥和无机肥+有机肥三种施肥方式条件下,根际土壤中氨氧化细菌、自生固氮菌和反硝化细菌三种不同生理菌群的变化。结果表明:施用无机肥条件下自然降水使氨氧化细菌数量高于充足水和干旱处理,干旱使好气性自生固氮菌和反硝化细菌数量高于自然降水和充足水,在自然降水条件不同施肥使功能性细菌发生变化,施肥促进三种功能菌的生长,其中,有机肥配施化肥的效果最为显著。反硝化细菌各处理数量相近,有机肥数量稍高