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1.
Alzheimer''s disease is the most common form of dementia. Abnormal hyperphosphorylation of Microtubule associated protein tau
(MAPT) is one of the hallmarks of Alzheimer''s disease and related tau pathies. CDK5 and GSK3B are the two main protein kinases
that have an important role in the abnormal hyperphosphorylation of MAPT which leads to Alzheimer''s disease. Structural
information for both MAPT-CDK5 and MAPT-GSK3B complexes being absent, we resorted to molecular modeling for gaining
insight into the mechanism of implication of hyperphosphorylation of MAPT by both enzymes. First the tertiary structure of MAPT
was modeled and its active regions were defined. This was followed by molecular docking and interaction studies of MAPT with
CDK5 and GSK3B kinases to infer the role of these kinases in abnormal hyperphosphorylation of MAPT protein. In addition, we
have investigated the characteristic features such as phosphorylation sites and ATP binding sites of MAPT and two kinases.
Further we computed the stabilization centers and stabilization residues of the MAPT protein and two kinases before and after
docking process. The overall results portray that CDK5 is strongly involved in the hyperphosphorylation of MAPT when
compared to GSK3B. 相似文献
2.
The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration
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Various neurodegenerative diseases are characterized by the accumulation of amyloidogenic proteins such as tau, α‐synuclein, and amyloid‐β. Prior to the formation of these stable aggregates, intermediate species of the respective proteins—oligomers—appear. Recently acquired data have shown that oligomers may be the most toxic and pathologically significant to neurodegenerative diseases such as Alzheimer's and Parkinson's. The covalent modification of these oligomers may be critically important for biological processes in disease. Ubiquitin and small ubiquitin‐like modifiers are the commonly used tags for degradation. While the modification of large amyloid aggregates by ubiquitination is well established, very little is known about the role ubiquitin may play in oligomer processing and the importance of the more recently discovered sumoylation. Many proteins involved in neurodegeneration have been found to be sumoylated, notably tau protein in brains afflicted with Alzheimer's. This evidence suggests that while the cell may not have difficulty recognizing dangerous proteins, in brains afflicted with neurodegenerative disease, the proteasome may be unable to properly digest the tagged proteins. This would allow toxic aggregates to develop, leading to even more proteasome impairment in a snowball effect that could explain the exponential progression in most neurodegenerative diseases. A better understanding of the covalent modifications of oligomers could have a huge impact on the development of therapeutics for neurodegenerative diseases. This review will focus on the proteolysis of tau and other amyloidogenic proteins induced by covalent modification, and recent findings suggesting a relationship between tau oligomers and sumoylation. 相似文献
3.
Pinning down phosphorylated tau and tauopathies 总被引:4,自引:0,他引:4
Neurofibrillary tangles (NFTs) are prominent neuronal lesions in a large subset of neurodegenerative diseases, including Alzheimer's disease (AD). NFTs are mainly composed of insoluble Tau that is hyperphosphorylated on many serine or threonine residues preceding proline (pSer/Thr-Pro). Tau hyperphosphorylation abolishes its biological function to bind microtubules and promotes microtubule assembly and precedes neurodegeneration. Not much is known about how tau is further regulated following phosphorylation. Notably, we have recently shown that phosphorylated Ser/Thr-Pro motifs exist in two distinct conformations. The conversion between two conformations in some proteins is catalyzed by the prolyl isomerase Pin1. Pin1 binds to tau phosphorylated specifically on the Thr231-Pro site and probably catalyzes cis/trans isomerization of pSer/Thr-Pro motif(s), thereby inducing conformational changes in tau. Such conformational changes can directly restore the ability of phosphorylated Tau to bind microtubules and promote microtubule assembly and/or facilitate tau dephosphorylation by its phosphatase PP2A, as PP2A activity is conformation-specific. Furthermore, Pin1 expression inversely correlates with the predicted neuronal vulnerability in normally aged brain and also with actual neurofibrillary degeneration in AD brain. Moreover, deletion of the gene encoding Pin1 in mice causes progressive age-dependent neuropathy characterized by motor and behavioral deficits, tau hyperphosphorylation, tau filament formation and neuronal degeneration. Distinct from all other mouse models where transgenic overexpression of specific proteins elicits tau-related pathologies, Pin1 is the first protein whose depletion causes age-dependent neurodegeneration and tau pathologies. Thus, Pin1 is pivotal in maintaining normal neuronal function and preventing age-dependent neurodegeneration. This could represent a promising interventive target to prevent neurodegenerative diseases. 相似文献
4.
Dongdong Zhao Yunqiang Zhou Yuanhui Huo Jian Meng Xiaoxia Xiao Linkun Han Xian Zhang Hong Luo Dan Can Hao Sun Timothy Y. Huang Xin Wang Jie Zhang Fa-rong Liu Huaxi Xu Yun-wu Zhang 《Cell death and differentiation》2021,28(1):337
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.Subject terms: Neural ageing, Neurological disorders 相似文献
5.
Oveis Karima Gholamhossein Riazi Sirus Khodadadi Hassan Aryapour Mohammad Ali Nasiri Khalili Leila Yousefi Ali Akbar Moosavi-Movahedi 《FEBS letters》2012,586(21):3914-3919
Tau isoforms promote neuronal integrity through binding and stabilization of microtubule proteins (MTP). It has been shown that hyperphosphorylation of tau contributes to Alzheimer’s disease (AD) pathology and related tauopathies. However, other pathogenic modifications of tau have not been well characterized. It is well accepted that elevated level of homocysteine (Hcy) is associated with neurodegenerative diseases such as AD. As a result of N-homocysteinylation of lysine residues, Hcy becomes a component of proteins, as a protein–homocystamide adduct, which affects protein structure and function. Here we demonstrate that N-homocysteinylation of human tau (4R/1N isoform) inhibits its function via impaired tau–tubulin specific binding and MTP assembly dynamics in vitro. 相似文献
6.
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。 相似文献
7.
神经退行性疾病如阿尔茨海默病、帕金森病、亨廷顿病等疾病的发生与氧化应激紧密相关。NAD和NADP是维持氧化系统和抗氧化系统平衡的两个关键物质。NAD和NADP的生物合成和降解有多种途径,参与其生物途径的物质如NAMPT、NADK、PARP1、SIRT1、CD38等,均报道在神经退行性疾病发挥一定的作用。因此,本文分别从NAD和NADP的合成和降解途径中的一些关键物质出发,结合氧化应激总结并探讨它们在神经退行性疾病的作用,以期为临床治疗神经退行性疾病提供新思路。 相似文献
8.
9.
Jianghao Zhao Xiaohui Li Xiongjin Chen Yujie Cai Yan Wang Wenjing Sun Hui Mai Jingqi Yang Weihao Fan Pei Tang Mingqian Ou Yuan Zhang Xuemei Huang Bin Zhao Lili Cui 《Journal of cellular physiology》2019,234(7):10411-10420
G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase whose dysfunction results in cognitive impairment and Alzheimer-like pathology, including tau hyperphosphorylation. However, the mechanisms whereby GRK5 influences tau phosphorylation remain incompletely understood. In the current study, we showed that GRK5 influenced the phosphorylation of tau via glycogen synthase kinase 3β (GSK3β). The activity of both tau and GSK3β in the hippocampus was increased in aged GRK5-knockout mice, which is consistent with what occurs in APP/PS1 transgenic mice. Furthermore, GRK5 regulated the activity of GSK3β and phosphorylated tau in vitro. Regardless of changes of GRK5 protein levels, tau hyperphosphorylation remained reduced after GSK3β activity was inhibited, suggesting that GRK5 may specifically influence tau hyperphosphorylation by modulating GSK3β activity. Taken together, our findings suggest that GRK5 deficiency contributes to the pathogenesis of Alzheimer's disease by influencing the hyperphosphorylation of tau through the activation of GSK3β. 相似文献
10.
Metals are essential for protein function as cofactors to catalyze chemical reactions. Disruption of metal homeostasis is implicated in a number of diseases including Alzheimer''s and Parkinson''s disease, but the exact role these metals play is yet to be fully elucidated. Identification of metalloproteins encounters many challenges and difficulties. Here we report an approach that allows metalloproteins in complex samples to be quantified. This is achieved using size exclusion chromatography coupled with inductively coupled plasma - mass spectrometry (SEC-ICP-MS). Using six known metalloproteins, the size exclusion column can be calibrated and the respective trace elements (iron, copper, zinc, cobalt, iodine) can be used for quantification. SEC-ICP-MS traces of human brain and plasma are presented. The use of these metalloprotein standards provides the means to quantitatively compare metalloprotein abundances between biological samples. This technique is poised to help shed light on the role of metalloproteins in neurodegenerative disease as well as other diseases where imbalances in trace elements are implicated. 相似文献
11.
Shaolong Zhu Agnesa Shala Alexandr Bezginov Adnan Sljoka Gerald Audette Derek J. Wilson 《PloS one》2015,10(3)
Tau is an intrinsically disordered protein (IDP) whose primary physiological role is to stabilize microtubules in neuronal axons at all stages of development. In Alzheimer''s and other tauopathies, tau forms intracellular insoluble amyloid aggregates known as neurofibrillary tangles, a process that appears in many cases to be preceded by hyperphosphorylation of tau monomers. Understanding the shift in conformational bias induced by hyperphosphorylation is key to elucidating the structural factors that drive tau pathology, however, as an IDP, tau is not amenable to conventional structural characterization. In this work, we employ a straightforward technique based on Time-Resolved ElectroSpray Ionization Mass Spectrometry (TRESI-MS) and Hydrogen/Deuterium Exchange (HDX) to provide a detailed picture of residual structure in tau, and the shifts in conformational bias induced by hyperphosphorylation. By comparing the native and hyperphosphorylated ensembles, we are able to define specific conformational biases that can easily be rationalized as enhancing amyloidogenic propensity. Representative structures for the native and hyperphosphorylated tau ensembles were generated by refinement of a broad sample of conformations generated by low-computational complexity modeling, based on agreement with the TRESI-HDX profiles. 相似文献
12.
帕金森病是中老年人常见的中枢神经系统退行性疾病,研究表明小胶质细胞的活化及其介导的神经炎症在帕金森病的病程进展中发挥重要作用,适度干预小胶质细胞的活化有望延缓帕金森病的进程。小胶质细胞是中枢神经系统固有的巨噬细胞,Notch信号途径可以调控小鼠外周巨噬细胞的分化及功能。Notch通路也参与调控小胶质细胞的激活、细胞因子的表达、吞噬活性的变化等,而这与活化的小胶质细胞介导的帕金森病等神经退行性疾病的病情进展相关。因此,本文将综述Notch信号途径与小胶质细胞介导的相关疾病的研究进展。 相似文献
13.
Yajie Wang Bufu Tang Jinyu Zhu Junchao Yu Junguo Hui Shuiwei Xia Jiansong Ji 《International journal of biological sciences》2022,18(10):4260
Ferroptosis is a novel type of cell death characterized by iron-dependent lipid peroxidation that involves a variety of biological processes, such as iron metabolism, lipid metabolism, and oxidative stress. A growing body of research suggests that ferroptosis is associated with cancer and neurodegenerative diseases, such as glioblastoma, Alzheimer''s disease, Parkinson''s disease, and stroke. Building on these findings, we can selectively induce ferroptosis for the treatment of certain cancers, or we can treat neurodegenerative diseases by inhibiting ferroptosis. This review summarizes the relevant advances in ferroptosis, the regulatory mechanisms of ferroptosis, the participation of ferroptosis in brain tumors and neurodegenerative diseases, and the corresponding drug therapies to provide new potential targets for its treatment. 相似文献
14.
糖酵解毒性副产物甲基乙二醛(methylglyoxal,MG)以其高反应活性在阿尔茨海默病(Alzheimer''s disease,AD)发生发展过
程中起到了重要的作用。MG 在AD病人脑中累积并促进beta淀粉样蛋白(beta-amyloid peptide,A beta)的产生和寡聚。大量累积的MG 通
过形成晚期糖基化终末产物(advanced glycosylation end products,AGEs)加剧了神经元中tau 蛋白的过度磷酸化。研究还发现MG
和AGEs 均参与了AD 脑中活性氧(reactive oxygen species,ROS)的产生和炎症的发生发展。本文总结了MG 在AD 病理过程中
的作用,并加以综述。 相似文献
15.
Estradiol Attenuates Tau Hyperphosphorylation Induced by Upregulation of Protein Kinase-A 总被引:1,自引:0,他引:1
Protein kinase A (PKA) plays a crucial role in tau hyperphosphorylation, an early event of Alzheimer disease (AD), and 17β-estradiol
replacement in aging women forestalls the onset of AD. However, the role of estradiol in PKA-induced tau hyperphosphorylation
is not known. Here, we investigated the effect of 17β-estradiol on cAMP/PKA activity and the PKA-induced tau hyperphosphorylation
in HEK293 cells stably expressing tau441. We found that 17β-estradiol effectively attenuated forskolin-induced overactivation
of PKA and elevation of cAMP, and thus prevented tau from hyperphosphorylation. These data provide the first evidence that
17β-estradiol can inhibit PKA overactivation and the PKA-induced tau hyperphosphorylation, implying a preventive role of 17β-estradiol
in AD-like tau pathology.
Xin-An Liu and Ling-Qiang Zhu contributed equally to this work. 相似文献
16.
Extracellular accumulations of Aβ, hyperphosphorylation of tau and intracellular neurofibrillary tangle formation have been
the hallmarks of Alzheimer’s Disease (AD). Although tau and its phosphorylation play a pivotal role in the normal physiology
yet its hyperphosphorylation has been a pathological manifestation in neurodegenerative disorders like AD. In this review
physiology of tau, its phosphorylation, hyperphosphorylation with the intervention of various kinases, aggregation and formation
of paired helical filaments has been discussed. A brief account of various animal models employed to study the pathological
manifestation of tau in AD and therapeutic strategies streamlined to counter the tau induced pathology has been given. The
reasons for the failure to have suitable animal model to study AD pathology and recent success in achieving this has been
included. The role of caspase cascade in tau cleavage has been emphasized. The summary of current studies on tau and the need
for future studies has been accentuated. 相似文献
17.
Amanda Cano Miren Ettcheto Mireia Bernuz Raquel Puerta Ester Esteban de Antonio Elena Snchez-Lpez Eliana B. Souto Antonio Camins Merc Martí María Isabel Pividori Merc Boada Agustín Ruiz 《International journal of biological sciences》2023,19(3):721
Extracellular vesicles are secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Their molecular cargo reflects the physiological processes that their cells of origin are undergoing. Thus, many studies have suggested that extracellular vesicles could be a promising biomarker tool for many diseases, mainly due to their biological relevance and easy accessibility to a broad range of body fluids. Moreover, since their biological composition leads them to cross the blood-brain barrier bidirectionally, growing evidence points to extracellular vesicles as emerging mirrors of brain diseases processes. In this regard, this review explores the biogenesis and biological functions of extracellular vesicles, their role in different physiological and pathological processes, their potential in clinical practice, and the recent outstanding studies about the role of exosomes in major human brain diseases, such as Alzheimer''s disease (AD), Parkinson''s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or brain tumors. 相似文献
18.
《生物化学与生物物理学报:疾病的分子基础》2014,1842(8):1282-1294
Parkinson's disease is a progressive neurodegenerative disease in the elderly, and no cure or disease-modifying therapies exist. Several lines of evidence suggest that mitochondrial dysfunction and oxidative stress have a central role in the dopaminergic neurodegeneration of Parkinson's disease. In this context, mitochondria-targeted therapies that improve mitochondrial function may have great promise in the prevention and treatment of Parkinson's disease. In this review, we discuss the recent developments in mitochondria-targeted antioxidants and their potential beneficial effects as a therapy for ameliorating mitochondrial dysfunction in Parkinson's disease. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases. 相似文献
19.
Zhiming Cui Tao Tao Chun Cheng Junling Yang Qin Shen Yuhong Ji Xiaohong Li Haiou Liu Aiguo Shen Xiang Lu 《Molecular and cellular biochemistry》2010,340(1-2):257-263
In Alzheimer’s disease, Beta-amyloid peptide (Aβ) could induce tau hyperphosphorylation which is the major cause of neuron apoptosis. However, the underlying mechanisms in the process remain unclear. In this study, Aβ-induced apoptosis and tau phosphorylation were investigated in differentiated PC12 cells. This Aβ-induced tau phosphorylation paralleled with the increase of expression and phosphorylation of Src-suppressed protein kinase C substrate (SSeCKS). By knocking down the expression of SSeCKS, Aβ-induced apoptosis and tau hyperphosphorylation in PC12 cells were partially rescued, and were increased further due to the overexpression of SSeCKS in PC12 cells. Also, the cell apoptosis and tau hyperphosphorylation were strongly decreased when the cells were pretreated with the protein kinase C inhibitor, Gö6983. In addition, Aβ-induced tau phosphorylation was also partially decreased due to the overexpression of SSeCKS in PC12cells. In summary, our data indicate that SSeCKS may play a critical role in Aβ-induced PC12 cells apoptosis through its phosphorylation. 相似文献
20.
The reversible phosphorylation of proteins regulates most biological processes, while abnormal phosphorylation is a cause or consequence of many diseases including Alzheimer''s disease (AD). One of the hallmarks of AD is the formation of neurofibrillary tangles (NFTs), which is composed of hyperphosphorylated tau proteins. Sodium selenate has been recently found to reduce tau hyperphosphorylation and NFTs formation, and to improve spatial learning and motor performance in AD mice. In the current study, the phosphoproteomics of N2aSW cells treated with selenate were investigated. To avoid missing low-abundance phosphoproteins, both the total proteins of cells and the phosphor-enriched proteins were extracted and subjected to the two-dimensional gel electrophoresis with Pro-Q diamond staining and then LC-MS/MS analysis. A total of 65 proteins were altered in phosphorylation level, of which 39 were up-regulated and 26 were down-regulated. All identified phosphoproteins were bioinformatically annotated according to their physiochemical features, subcellular location, and biological function. Most of these significantly changed phosphoproteins are involved in crucial neural processes such as protesome activity, oxidative stress, cysteine and methionine metabolism, and energy metabolism. Furthermore, decreases were found in homocysteine, phosphor-tau and amyloid β upon selenate treatment. Our results suggest that selenate may intervene in the pathological process of AD by altering the phosphorylation of some key proteins involved in oxidative stress, energy metabolism and protein degradation, thus play important roles in maintaining redox homeostasis, generating ATP, and clearing misfolded proteins and aggregates. The present paper provides some new clues to the mechanism of selenate in AD prevention. 相似文献