SUMO在阿尔茨海默症及其运动干预调节中的作用

阿尔茨海默症(Alzheimer's diseases, AD)是一种常见的神经退行性疾病,俗称老年性痴呆。脑内Aβ过度聚集、Tau蛋白过度磷酸化和神经元凋亡是AD的主要病理特征。小泛素样修饰蛋白(small ubiquitin-like modifier, SUMO)通过与底物蛋白结合参与蛋白质翻译后修饰,已被发现可通过以下方式参与AD的病理过程,主要有:(1) SUMO修饰BACE1,促进Aβ产生;(2) SUMO修饰Tau蛋白,促进其磷酸化并抑制其被泛素蛋白酶系统降解;(3) AD脑内SUMO化异常导致神经元过度凋亡。运动已被证实可改善AD病理特征,调节体内SUMO化水平,这提示运动缓解AD可能存在SUMO化机制。现通过综述SUMO与AD,以及运动对SUMO的影响,阐述SUMO介导的运动抗AD的可能机制。     

SUMO化和磷酸化的相互作用和共同修饰

翻译后修饰如磷酸化、乙酰化、甲基化、泛素化和SUMO化调节不同蛋白质的不同功能。磷酸化可能是最常见的修饰之一,蛋白质磷酸化通过一系列的激酶和磷酸酶催化,从而改变蛋白质功能。SUMO修饰是一种类泛素化修饰。SUMO修饰包括活化、结合、连接和解离,涉及多个酶多个步骤的催化过程。SUMO化可调节蛋白质相互作用、亚细胞定位、蛋白质稳定性和转录活性。关于磷酸化和SUMO化的蛋白质翻译后修饰,已有广泛研究报道。但很少关注于磷酸化和SUMO化之间的相互作用,以及它们对蛋白质的共同修饰。本文综述了蛋白质磷酸化和SUMO化之间的相互作用,以及共同修饰对细胞生理和肿瘤的影响。     

SUMO化和磷酸化的相互作用与共同修饰

翻译后修饰如磷酸化、乙酰化、甲基化、泛素化和SUMO化调节不同蛋白质的不同功能。磷酸化可能是最常见的修饰之一,蛋白质磷酸化通过一系列的激酶和磷酸酶催化,从而改变蛋白质功能。SUMO修饰是一种类泛素化修饰。SUMO修饰包括活化、结合、连接和解离,涉及多个酶多个步骤的催化过程。SUMO化可调节蛋白质相互作用、亚细胞定位、蛋白质稳定性和转录活性。关于磷酸化和SUMO化的蛋白质翻译后修饰,已有广泛研究报道。但很少关注于磷酸化和SUMO化之间的相互作用,以及它们对蛋白质的共同修饰。本文综述了蛋白质磷酸化和SUMO化之间的相互作用,以及共同修饰对细胞生理和肿瘤的影响。     

有丝分裂期间蛋白质的翻译后修饰及其功能

有丝分裂期间蛋白质的翻译后修饰对于有丝分裂顺利完成以及细胞功能发挥具有重要的调控作用。常见的修饰类型包括磷酸化修饰、糖基化修饰、SUMO化修饰、乙酰化修饰、甲基化修饰。这些翻译后修饰可以维持染色体结构、促进后期染色体分离、协助末期核膜重新形成。本文对有丝分裂过程中相关蛋白质翻译后修饰的最新类型和功能进行了系统总结,以期能为肿瘤基础研究提供新的方向。     

罗格列酮对AD样小鼠学习记忆减退的影响及机制

研究了罗格列酮对链脲佐菌素(streptozotocin, STZ)脑室内注射的阿尔茨海默病(AD)模型小鼠学习记忆减退的影响及机制．在小鼠脑室内注射STZ建立AD模型,治疗组小鼠采用罗格列酮灌胃给药30天．Morris水迷宫实验检测小鼠学习记忆能力,免疫印迹和免疫荧光检测Tau蛋白的磷酸化、神经丝(NFs)蛋白的磷酸化及糖基化、JNK和ERK蛋白的表达,微管结合实验检测Tau蛋白与微管的组装功能,荧光染料Fluoro-Jade B检测小鼠脑内退变神经元．结果显示,相比对照组,模型组小鼠平均逃避潜伏期和路径长度明显增加、穿越隐匿平台次数明显减少、Tau和NFs蛋白表达过度磷酸化、NFs蛋白糖基化减弱,而用罗格列酮干预的小鼠学习记忆改善并且Tau和NFs蛋白的磷酸化水平降低、NFs蛋白糖基化水平增加,Tau蛋白与微管结合能力改善,模型组JNK的磷酸化高于对照组和治疗组、模型组ERK1的磷酸化低于对照组和治疗组、各组在ERK2磷酸化无明显差异,模型组小鼠脑中FJB标记的退化神经元明显多于对照组和治疗组．结果说明,罗格列酮能改善STZ脑室内注射引起的小鼠学习记忆减退,其机制可能与改善胰岛素信号通路、降低Tau和NFs蛋白的过度磷酸化、减少神经退行性变有关．     

阿尔次海默病tau蛋白异常修饰与其功能的关系

阿尔次海默病易溶型胞浆tau和难溶型双螺旋丝中的tau均被异常磷酸化和异常糖基化修饰.异常修饰的tau丧失其促微管组装活性,用不同蛋白磷酸酯酶对难溶型双螺旋丝中的tau去磷酸化处理后可不同程度恢复其促微管组装生物学活性.单纯去糖基化处理只在很小限度恢复tau的功能,但去糖基化预处理可增强去磷酸化对tau上述活性的恢复.提示:a.tau的异常磷酸化是导致其功能活性丧失的直接因素,而糖基化修饰可能通过对其结构的影响而间接对tau功能活性发挥作用;b.蛋白磷酸酯酶可部分抑制和逆转阿尔次海默病的脑病理损伤.     

tau蛋白异常翻译后修饰在阿尔茨海默病中的作用

在阿尔茨海默病（A1zheimer’s disease,AD）中微管相关蛋白tau能够产生许多异常翻译后修饰并聚集形成配对螺旋丝（paired helical filament,PHF）。这些tau的修饰包括过磷酸化、异常糖基化、截断等,其中,过磷酸化和异常糖基化是阿尔茨海默氏病等神经退行性疾病神经元纤维化的主要分子发病机制。     

PP2A在运动抗阿尔茨海默病进程中的机制研究

Tau蛋白过度磷酸化是AD发病的重要原因,促进脑中p-Tau蛋白的脱磷酸化进程是运动抗AD的重要途径。PP2A是重要的蛋白磷酸酶,对p-Tau蛋白的脱磷酸化有重要作用。有关PP2A介导运动抗AD的Tau蛋白磷酸化机制研究尚不多见。现从Tau蛋白与AD研究、PP2A与AD研究、运动与AD研究、PP2A与运动抗AD研究等方面,系统阐述PP2A在介导运动抗AD进程中的蛋白磷酸化机制,为探明运动抗AD的Tau蛋白途径及运动促进健康的蛋白质修饰机制研究提供参考。     

综述:Tau蛋白过度磷酸化机制及其在阿尔茨海默病神经元变性中的作用

Tau蛋白是神经元中含量最高的微管相关蛋白,其经典生物学功能是促进微管组装和维持微管的稳定性．在阿尔茨海默病(Alzheimer's disease,AD)患者,异常过度磷酸化的Tau蛋白以配对螺旋丝结构形成神经原纤维缠结并在神经元内聚积．大量研究提示,Tau蛋白异常在AD患者神经变性和学习记忆障碍的发生发展中起重要作用．本课题组对Tau蛋白异常磷酸化的机制及其对细胞的影响进行了系列研究,发现Tau蛋白表达和磷酸化具有调节细胞生存命运的新功能,并由此对AD神经细胞变性的本质提出了新见解．本文主要综述作者实验室有关Tau蛋白的部分研究结果．     

小泛素相关修饰物SUMO研究进展

蛋白质翻译后修饰对改变蛋白功能、活性或定位都起着非常重要的作用,泛素及其相似蛋白的修饰是其中一种重要形式。与其他诸如磷酸化、乙酰化、糖基化等不同的是,泛素及其相似蛋白的修饰基团本身即是一个小的多肽,通过异肽键与靶蛋白Lys侧链ε-NH2相连,其中小泛素相关修饰物(small ubiquitin—related modifier,SUMO)与蛋白的共价连接是一种新的广泛存在的翻译后修饰形式。SUMO是广泛存在于真核生物中高度保守的蛋白家族,在脊椎动物中有三个SUMO基因,称为SUMO-1,-2,-3,与泛素在二级结构上极其相似,且催化修饰过程的酶体系也具有很高的同源性。然而,与泛素化介导的蛋白酶降解途径不同,SUMO化修饰发挥着更为广泛的功能,如核质转运、细胞周期调控、信号转导、转录活性调控等。     

Tau蛋白寡聚体与阿尔茨海默病

阿尔茨海默病（AD）是严重影响老年人健康的一种神经退行性疾病。AD主要两个病理特征是tau蛋白组成的神经原纤维缠结和β淀粉样蛋白组成的Aβ斑块。Tau蛋白是目前研究AD机制和防治药物的一个重要靶点。Tau蛋白的寡聚体形式被认为是最具神经毒性的,并且其能在神经元之间传播,诱导胞内的正常tau蛋白聚集。本综述结合近年来的文献报道,对tau寡聚体的制备手段、形成机理、神经毒性、传播机制以及治疗前景等方面做了系统总结和讨论,为人们深入认识tau寡聚体提供参考。     

Acetylation as a major determinant to microtubule-dependent autophagy: Relevance to Alzheimer's and Parkinson disease pathology

Protein post-translational modifications (PTMs) that potentiate protein aggregation have been implicated in several neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD). In fact, Tau and alpha-synuclein (ASYN) undergo several PTMs potentiating their aggregation and neurotoxicity.Recent data posits a role for acetylation in Tau and ASYN aggregation. Herein we aimed to clarify the role of Sirtuin-2 (SIRT2) and HDAC6 tubulin deacetylases as well as p300 acetyltransferase in AD and PD neurodegeneration. We used transmitochondrial cybrids that recapitulate pathogenic alterations observed in sporadic PD and AD patient brains and ASYN and Tau cellular models.We confirmed that Tau protein and ASYN are microtubules (MTs)-associated proteins (MAPs). Moreover, our results suggest that α-tubulin acetylation induced by SIRT2 inhibition is functionally associated with the improvement of MT dynamic determined by decreased Tau phosphorylation and by increased Tau/tubulin and ASYN/tubulin binding. Our data provide a strong evidence for a functional role of tubulin and MAPs acetylation on autophagic vesicular traffic and cargo clearance. Additionally, we showed that an accumulation of ASYN oligomers imbalance mitochondrial dynamics, which further compromise autophagy. We also demonstrated that an increase in Tau acetylation is associated with Tau phosphorylation. We found that p300, HDAC6 and SIRT2 influences Tau phosphorylation and autophagic flux in AD. In addition, we demonstrated that p300 and HDAC6 modulate Tau and Tubulin acetylation.Overall, our data disclose the role of Tau and ASYN modifications through acetylation in AD and PD pathology, respectively. Moreover, this study indicates that MTs can be a promising therapeutic target in the field of neurodegenerative disorders in which intracellular transport is altered.     

Post-translational modifications of tau protein: implications for Alzheimer's disease

Alzheimer's disease (AD) belongs to a group of neurodegenerative diseases collectively designated as "tauopathies", because they are characterized by the aggregation of abnormally phosphorylated tau protein. The mechanisms responsible for tau aggregation and its contribution to neurodegeneration are still unknown. Thereby, understanding the modes of regulation of tau is of high interest in the determination of the possible causes at the origin of the formation of tau aggregates and to elaborate protection strategies to cope with these pathological lesions. The regulation of tau takes place predominantly through post-translational modifications. Extensive reports have been published about tau phosphorylation; however, the other tau post-translational modifications have received much less attention. Here, we review the different types of post-translational modifications of tau including phosphorylation, glycosylation, glycation, prolyl-isomerization, cleavage or truncation, nitration, polyamination, ubiquitination, sumoylation, oxidation and aggregation, with a particular interest towards their relevance in AD.     

Tau蛋白在阿尔茨海默病中的作用

阿尔茨海默病(AD)是非常普遍的神经变性性疾病并且是老年人痴呆的主要原因。AD患者的症状特点包括进行性的认知障碍、记忆丧失和行为障碍,与大脑中的病理变化密切相关。AD现成为全球最严重的健康和社会经济问题。在AD患者脑中神经纤维网或神经营养障碍的过程中存在tau蛋白的异常。tau蛋白丧失其促微管组装的生物学功能,导致细胞骨架的破坏、丝状物形成和神经缠结,轴突运输损害,进而导致突触蛋白失去功能和神经退行性病变。其数量和结构的改变将会影响其功能而且会出现异常聚集。调节Tau蛋白的异常聚集的分子机制主要是一些翻译后修饰使其结构及构象发生变化。因此,异常磷酸化和截断的tau蛋白作为tau蛋白病理过程的关键机制而引起学者关注。本文描述了tau蛋白的结构和功能及其在AD中的主要病理变化,同时在本文中还涉及到磷酸化的tau蛋白是神经元对氧化应激的代偿反应这一观点。对tau蛋白进行更加全面的解读。     

Histone deacetylase-6 modulates Tau function in Alzheimer's disease

Alzheimer's disease (AD), one of the major tauopathies, is multifactorial with a massive demand for disease-modifying treatments rather than symptom management. An AD-affected neuron shows Tau depositions generated due to overload on the proteostasis machinery of the cell and/or abnormal post-translational modifications on Tau protein. Loss of memory or dementia is the most significant concern in AD, occurring due to the loss of neurons and the connections between them. In a healthy brain, neurons interact with the environment and each other through extensions and migratory structures. It can thus be safe to assume that Tau depositions affect these growth structures in neurons. A Histone Deacetylase, HDAC6, has shown elevated levels in AD while also demonstrating direct interaction with the Tau protein. HDAC6 interacts with multiple proteins in the cell and is possibly involved in various signalling pathways. Its deacetylase activity has been a point of controversy in AD; however other functional domains remain unexplored. This review highlights the beneficial potential of HDAC6 in AD in mediating both Tau proteostasis and cytoskeletal rewiring for the neuritic extensions through its Ubiquitin Binding domain (HDAC6 ZnF UBP).     

Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein

Sumoylation is an important post-translational modification that provides a rapid and reversible means for controlling the activity, subcellular localization, and stability of target proteins. We have examined the covalent attachment of the small ubiquitin-like modifier (SUMO) proteins to tau and alpha-synuclein, two natively unfolded proteins that define several neurodegenerative diseases. Both brain proteins were preferentially modified by SUMO1, as compared with SUMO2 or SUMO3. Tau contains two SUMO consensus sequences, and mutational analyses identified Lys(340) as the major sumoylation site. Although both tau and alpha-synuclein are targets for proteasomal degradation, only tau sumoylation was affected by inhibitors of the proteasome pathway. Tau is a microtubule-associated protein, whose ability to bind and stabilize microtubules is negatively regulated by phosphorylation. Treatment with the phosphatase inhibitor, okadaic acid, or the microtubule depolymerizing drug, colchicine, up-regulated tau sumoylation. This suggests that SUMO modification may preferentially target a free soluble pool of the substrate. These findings revealed a new, possibly regulatory, modification of tau and alpha-synuclein that may also have implications for their pathogenic roles in neurodegenerative diseases.     

Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function

The presence of tangles composed of phosphorylated tau is one of the neuropathological hallmarks of Alzheimer''s disease (AD). Tau, a microtubule (MT)-associated protein, accumulates in AD potentially as a result of posttranslational modifications, such as hyperphosphorylation and conformational changes. However, it has not been fully understood how tau accumulation and phosphorylation are deregulated. In the present study, we identified a novel role of death-associated protein kinase 1 (DAPK1) in the regulation of the tau protein. We found that hippocampal DAPK1 expression is markedly increased in the brains of AD patients compared with age-matched normal subjects. DAPK1 overexpression increased tau protein stability and phosphorylation at multiple AD-related sites. In contrast, inhibition of DAPK1 by overexpression of a DAPK1 kinase-deficient mutant or by genetic knockout significantly decreased tau protein stability and abolished its phosphorylation in cell cultures and in mice. Mechanistically, DAPK1-enhanced tau protein stability was mediated by Ser71 phosphorylation of Pin1, a prolyl isomerase known to regulate tau protein stability, phosphorylation, and tau-related pathologies. In addition, inhibition of DAPK1 kinase activity significantly increased the assembly of MTs and accelerated nerve growth factor-mediated neurite outgrowth. Given that DAPK1 has been genetically linked to late onset AD, these results suggest that DAPK1 is a novel regulator of tau protein abundance, and that DAPK1 upregulation might contribute to tau-related pathologies in AD. Therefore, we offer that DAPK1 might be a novel therapeutic target for treating human AD and other tau-related pathologies.     

Acetylation and phosphorylation processes modulate Tau’s binding to microtubules: A molecular dynamics study

The microtubule-associated protein Tau has its normal function impaired when undergoing post-translational modifications. In this work, molecular modelling techniques were used to infer the effects of acetylation and phosphorylation in Tau's overall conformation, electrostatics, and interactions, but mostly in Tau's ability to bind microtubules. Reported harmful Lys sites were mutated by its acetylated form, generating eight different acetylated Tau (aTau) analogues. Similarly, phosphorylation sites found in normal brains and in Alzheimer’s lesioned brains were considered to design phosphorylated Tau (pTau) analogues. All these designed variants were evaluated in intracellular fluid and near a microtubule (MT) model. Our in silico findings demonstrated that the electrostatic changes, due to the absence of positive Lys’ charges in acetylation cases, or the increasingly negative charge in the phosphorylated forms, hamper the association to the MT tubulins in most cases. Post-translational modifications also pose very distinct conformations to the ones described for native Tau, which hinders the microtubule-binding region (MTBR) and turns difficult the expected binding. Our study elucidates important molecular processes behind Tau abnormal function which can inspire novel therapeutics to address Alzheimer’s disease.