Huntingtin聚合与Huntington舞蹈病

许多神经退行性疾病是由蛋白质错误折叠导致的。Huntington舞蹈病(HD)是由蛋白质多聚谷氨酰胺延长引起的9种疾病之一,含延长多聚谷氨酰胺序列的蛋白质聚集在中枢神经系统的神经元中形成包涵体(inclusions)和聚集体(aggregates)。本文综述了Huntingtin蛋白错误折叠和聚集的机制以及疾病治疗的有关研究进展。     

神经分子影像：阿尔茨海默病的动态神经病理

正神经退行性疾病多数是一个或多个折叠或错误折叠的病理性积累,与聚集的蛋白质相关。既往唯一确定诊断方法是尸检(神经病理)来确认这些异常蛋白质沉积或病理变化的存在。尸检或活检发现这种特征性病理改变是诊断疾病的必要条件。如果能在早期发现确诊,即在疾病的不可逆性改变之前可能会得到更好     

活性氮在神经退行性疾病自噬病理环节中的作用

正蛋白质的异常折叠与聚集是神经退行性疾病中常见的共同特征之一,目前,对公认的神经退行性疾病,诸如阿尔茨海默病(Alzheimer disease,AD)的脑病理学研究发现,神经元淀粉样斑块沉积由错误折叠的β淀粉样肽(amyloid-beta peptide,Aβ)聚集物和含有微管相关蛋白Tau(microtubuleassociated protein Tau,Tau)的神经纤维缠结(neurofibrillary     

自噬及其在亨廷顿舞蹈病发病机制中的作用

自噬是真核生物中的一种维持细胞基本功能的生命现象。最近研究结果显示,自噬在清除与神经变性疾病相关的错误折叠蛋白和易聚集蛋白方面起关键作用。Huntington舞蹈病(HD)是由CAG三核苷酸重复突变引起的神经变性疾病,含延长多聚谷氨酰胺序列的蛋白质聚集在中枢神经系统的神经元中形成包涵体和聚集体,从而导致疾病的发生。该文综述了自噬及其在HD发病机制中的作用。     

未折叠蛋白反应及其在生理功能与疾病中的作用

未折叠或错误折叠的蛋白质在内质网(endoplasmic reticulum,ER)中聚集促使细胞做出适应性反应,包括上调位于内质网的各种酶和分子伴侣,这被称为未折叠蛋白反应(unfolded protein response,UPR)。未折叠蛋白反应存在于所有的真核细胞中,是人们了解最多的细胞器间信号传导系统模型。未折叠蛋白反应信号传导的基本机制最先在酵母中被阐明,在哺乳动物中有类似机制但表现得更为复杂。目前已经知道哺乳动物中有三条途径涉及UPR信号传导,分别是IRE1-XBP1路径,ATF6路径和PERK-elF2α磷酸化-ATF4路径。UPR在细胞生理病理中发挥重要作用。很多疾病如神经退行性疾病、糖尿病与高同型半胱氨酸血症等与蛋白折叠错误及由此引起的UPR有关。这些疾病也被称为错误折叠蛋白疾病。     

mTOR信号通路与自噬在神经退行性疾病中的 研究进展

哺乳动物雷帕霉素靶蛋白（mTOR）是一种保守的丝氨酸/ 苏氨酸激酶，mTOR 在上游信号 分子Rheb、TSC1/2 的调控下使下游4E-BP和p70S6K 做出相应的反应，进而影响蛋白质合成来调节细胞 生长和增殖。自噬是细胞的一种自我保护机制，神经退行性疾病中某些聚集蛋白的清除主要依靠自噬 来完成。近些年研究表明，诸如阿尔茨海默病等神经退行性疾病与甲状腺功能、mTOR信号通路和自噬 的异常有关。因此，对甲状腺功能、mTOR 通路及自噬的研究有助于了解神经退行性疾病的发生机制， 以更好预防和治疗该疾病。     

抗氧化剂对阿尔茨海默症自噬的调控作用及机制

<正>神经退行性疾病阿尔茨海默症(Alzheimer disease,AD)的特点之一是大量错误折叠的蛋白在神经细胞中异常聚集,引发多种神经功能障碍。自噬是细胞的一种饥饿应答,通过溶酶体或液泡将衰老或受损的细胞器以及形态、功能异常的大分子降解以循环利用,维持细胞内环境相对稳定的生理过程。因此,在AD的早期,自噬通过清除错误折叠、异常聚集的蛋白而具有重要的保护作用。然而,在AD的晚期,过度激活的自噬会导致细胞的损伤而引起疾病的恶化,因此,研究自噬在AD发病过程中的作用与机制对于疾病的治疗具有重要作用。     

关注铁过量与神经退行性疾病

神经退行性疾病是一组大脑和脊髓神经元丧失的疾病,其中阿尔茨海默病(Alzheimer disease,AD)和帕金森症病(Parkinson disease,PD)分别为认知障碍和运动障碍两大类疾病的典型代表。目前有关诱导这类神经疾病发生的因素尚不完全明确。近年研究表明,除蛋白异常聚集之外,大脑中微量元素铁的过度沉积及其相关联的氧化应激效     

液-液相分离介导的蛋白质稳态调控在神经退行性疾病中的研究进展

近十年来众多研究已经提示液-液相分离(LLPS)可以通过介导免疫炎症、转录调控、蛋白质稳态、基因组稳定性、氧化应激等途径参与神经退行性疾病的发生及进展, 其中以LLPS介导的蛋白质稳态调控尤其受到关注。笔者现围绕近年来LLPS介导的蛋白质稳态调控在神经退行性疾病发生中的机制研究进展进行综述, 并对LLPS相关研究进行展望。     

NLRP3在帕金森病中的相关研究进展

正帕金森病(Parkinson disease,PD)是由于中脑黑质多巴胺能神经元变性死亡及路易小体(Lewybody,LB)的形成而导致的一种进行性神经退行性疾病~[1],目前认为相关病因可能与以下因素有关:氧化应激、线粒体功能障碍、α-突触核蛋白(α-synuclein)的错误折叠和慢性神经炎症等因素~[2,3]。在PD早期,神经炎症将会逐渐加速疾病的进展。有研究表明,在由神经炎症介导的神经退行性疾病中,核苷酸结合寡聚化结构域样受体热蛋白结构域3(Nucleotidebinding and oligomerization domain-like receptor pyrin domain containing three,NLRP3)激活的炎症小体和小胶质细胞以及释放的白细胞介素(Interleukin,IL)-1β(IL-1β)等炎性细胞因子起着重要的作     

Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases

Protein misfolding and aggregation in the brain have been recognized to be crucial in the pathogenesis of various neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and the polyglutamine (polyQ) diseases, which are collectively called the “protein misfolding diseases”. In the polyQ diseases, an abnormally expanded polyQ stretch in the responsible proteins causes the proteins to misfold and aggregate, eventually resulting in neurodegeneration. Hypothesizing that polyQ protein misfolding and aggregation could be inhibited by molecules specifically binding to the expanded polyQ stretch, we identified polyQ binding peptide 1 (QBP1). We show that QBP1 does, indeed, inhibit misfolding and aggregation of the expanded polyQ protein in vitro. Furthermore overexpression of QBP1 by the crossing of transgenic animals inhibits neurodegeneration in Drosophila models of the polyQ diseases. We also introduce our attempts to deliver QBP1 into the brain by administration using viral vectors and protein transduction domains. Interestingly, recent data suggest that QBP1 can also inhibit the misfolding/aggregation of proteins responsible for other protein misfolding diseases, highlighting the potential of QBP1 as a general therapeutic molecule for a wide range of neurodegenerative diseases. We hope that in the near future, aggregation inhibitor-based drugs will be developed and bring relief to patients suffering from these currently intractable protein misfolding diseases.     

Mechanisms of disease II: cellular protein quality control

Protein misfolding and aggregation are common to many disorders, including neurodegenerative diseases referred to as "conformational disorders," suggesting that alterations in the normal protein homeostasis might contribute to pathogenesis. Cells evolved 2 major components of the protein quality control system to deal with misfolded and/or aggregated proteins: molecular chaperones and the ubiquitin proteasome pathway. Recent studies have implicated components of both systems in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, or the prion diseases. A detailed understanding of how the cellular quality control systems relate to neurodegeneration might lead to the development of novel therapeutic approaches for disorders associated with protein misfolding and aggregation.     

Autophagy and its neuroprotection in neurodegenerative diseases

It has been suggested that protein misfolding and aggregation contribute significantly to the development of neurodegenerative diseases.Misfolded and aggregated proteins are cleared by ubiquitin proteasomal system (UPS) and by both Micro and Macro autophagy lysosomal pathway (ALP).Autophagosomal dysfunction has been implicated in an increasing number of diseases including neurodegenerative diseases.Autophagy is a cellular self-eating process that plays an important role in neuroprotection as well as neuronal injury and death.While a decrease in autophagic activity interferes with protein degradation and possibly organelle turnover,increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival in a number of disease models.On the other hand,too much autophagic activity can be detrimental,suggesting the regulation of autophagy is critical in dictating cell fate.In this review paper,we will discuss various aspects of ALP biology and its dual functions in neuronal cell death and survival.We will also evaluate the role of autophagy in neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,amyotrophic lateral sclerosis.Finally,we will explore the therapeutic potential of autophagy modifiers in several neurodegenerative diseases.     

Cell-to-cell transmission of non-prion protein aggregates

Neurodegenerative disorders such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and Creutzfeldt-Jakob disease (CJD) are characterized by progressive accumulation of protein aggregates in selected brain regions. Protein misfolding and templated assembly into aggregates might result from an imbalance between protein synthesis, aggregation and clearance. Although protein misfolding and aggregation occur in most neurodegenerative disorders, the concept of spreading and infectivity of aggregates in the CNS has, until now, been confined to prion diseases such as CJD and bovine spongiform encephalopathy. Emerging evidence, however, suggests that prion-like spreading, involving secreted proteins such as amyloid-β and cytosolic proteins such as tau, huntingtin and α-synuclein, can occur in other neurodegenerative disorders. The underlying molecular mechanisms and the therapeutic implications of the new data are discussed in this article.     

Protein misfolding and neurodegeneration

A key molecular pathway implicated in diverse neurodegenerative diseases is the misfolding, aggregation, and accumulation of proteins in the brain. Compelling evidence strongly supports the hypothesis that accumulation of misfolded proteins leads to synaptic dysfunction, neuronal apoptosis, brain damage, and disease. However, the mechanism by which protein misfolding and aggregation trigger neurodegeneration and the identity of the neurotoxic structure is still unclear. The aim of this article is to review the literature around the molecular mechanism and role of misfolded protein aggregates in neurodegeneration and the potential for the misfolding process to lead to a transmissible form of disease by a prion-based model of propagation.     

Infectious prion protein alters manganese transport and neurotoxicity in a cell culture model of prion disease

Protein misfolding and aggregation are considered key features of many neurodegenerative diseases, but biochemical mechanisms underlying protein misfolding and the propagation of protein aggregates are not well understood. Prion disease is a classical neurodegenerative disorder resulting from the misfolding of endogenously expressed normal cellular prion protein (PrP(C)). Although the exact function of PrP(C) has not been fully elucidated, studies have suggested that it can function as a metal binding protein. Interestingly, increased brain manganese (Mn) levels have been reported in various prion diseases indicating divalent metals also may play a role in the disease process. Recently, we reported that PrP(C) protects against Mn-induced cytotoxicity in a neural cell culture model. To further understand the role of Mn in prion diseases, we examined Mn neurotoxicity in an infectious cell culture model of prion disease. Our results show CAD5 scrapie-infected cells were more resistant to Mn neurotoxicity as compared to uninfected cells (EC(50)=428.8 μM for CAD5 infected cells vs. 211.6 μM for uninfected cells). Additionally, treatment with 300 μM Mn in persistently infected CAD5 cells showed a reduction in mitochondrial impairment, caspase-3 activation, and DNA fragmentation when compared to uninfected cells. Scrapie-infected cells also showed significantly reduced Mn uptake as measured by inductively coupled plasma-mass spectrometry (ICP-MS), and altered expression of metal transporting proteins DMT1 and transferrin. Together, our data indicate that conversion of PrP to the pathogenic isoform enhances its ability to regulate Mn homeostasis, and suggest that understanding the interaction of metals with disease-specific proteins may provide further insight to protein aggregation in neurodegenerative diseases.     

Gene Therapy for Misfolding Protein Diseases of the Central Nervous System

Protein aggregation as a result of misfolding is a common theme underlying neurodegenerative diseases. Accordingly, most recent studies aim to prevent protein misfolding and/or aggregation as a strategy to treat these pathologies. For instance, state-of-the-art approaches, such as silencing protein overexpression by means of RNA interference, are being tested with positive outcomes in preclinical models of animals overexpressing the corresponding protein. Therapies designed to treat central nervous system diseases should provide accurate delivery of the therapeutic agent and long-term or chronic expression by means of a nontoxic delivery vehicle. After several years of technical advances and optimization, gene therapy emerges as a promising approach able to fulfill those requirements. In this review we will summarize the latest improvements achieved in gene therapy for central nervous system diseases associated with protein misfolding (e.g., amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases), as well as the most recent approaches in this field to treat these pathologies.     

Protein misfolding in neurodegenerative diseases

A common pathogenic mechanism shared by diverse neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease and transmissible spongiform encephalopathies, may be altered protein homeostasis leading to protein misfolding and aggregation of a wide variety of different proteins in the form of insoluble fibrils. Mutations in the genes encoding protein constituents of these aggregates have been linked to the corresponding diseases, thus a reasonable scenario of pathogenesis was based on misfolding of a neurone-specific protein that forms insoluble fibrils that subsequently kill neuronal cells. However, during the past 5 years accumulating evidence has revealed the neurotoxic role of prefibrillar intermediate forms (soluble oligomers and protofibrils) produced during fibril formation. Many think these may be the predominant neurotoxic species, whereas microscopically visible fibrillar aggregates may not be toxic. Large protein aggregates may rather be simply inactive, or even represent a protective state that sequesters and inactivates toxic oligomers and protofibrils. Further understanding of the biochemical mechanisms involved in protein misfolding and fibrillization may optimize the planning of common therapeutic approaches for neurodegenerative diseases, directed towards reversal of protein misfolding, blockade of protein oligomerization and interference with the action of toxic proteins.     

Protein aggregation,misfolding and consequential human neurodegenerative diseases

Proteins are major components of the biological functions in a cell. Biology demands that a protein must fold into its stable three-dimensional structure to become functional. In an unfavorable cellular environment, protein may get misfolded resulting in its aggregation. These conformational disorders are directly related to the tissue damage resulting in cellular dysfunction giving rise to different diseases. This way, several neurodegenerative diseases such as Alzheimer, Parkinson Huntington diseases and amyotrophic lateral sclerosis are caused. Misfolding of the protein is prevented by innate molecular chaperones of different classes. It is envisaged that work on this line is likely to translate the knowledge into the development of possible strategies for early diagnosis and efficient management of such related human diseases. The present review deals with the human neurodegenerative diseases caused due to the protein misfolding highlighting pathomechanisms and therapeutic intervention.     

Cyclic amplification of protein misfolding: application to prion-related disorders and beyond

Diverse human disorders, including the majority of neurodegenerative diseases, are thought to arise from the misfolding and aggregation of protein. We have recently described a novel technology to amplify cyclically misfolded proteins in vitro. This procedure, named protein misfolding cyclic amplification (PMCA), is conceptually analogous to DNA amplification by PCR and has tremendous implications for research and diagnosis. The PMCA concept has been proved on the amplification of prions implicated in the pathogenesis of transmissible spongiform encephalopathies. In this article we describe the rational behind PMCA and some of the many potential applications of this novel technology.