神经干细胞移植在神经退行性疾病中的研究进展

神经退行性疾病是一类可导致感觉丧失、运动功能丧失和记忆衰竭等症状的难治性疾病,传统治疗方法虽能延缓疾病进展,但局限性明显。而神经干细胞移植作为一种潜在的新型治疗方式能够有效促进神经细胞的功能恢复及组织再生,在神经退行性疾病的治疗应用方面前景广阔。因此,本文通过对神经干细胞的现有来源及其在神经退行性疾病治疗中的研究进展进行综述,以期为神经干细胞移植在神经退行性疾病治疗中的应用提供新的思路。     

干细胞与神经退行性疾病

神经退行性疾病是一类以神经元退行性病变或凋亡, 从而导致个体行为异常乃至死亡为主要特征的疾病. 随着社会逐渐步入老龄化, 神经退行性疾病的发病率不断攀升, 而大多这类疾病诊断困难, 目前尚无有效的治疗措施. 干细胞研究的迅速发展, 为这类疾病的治疗提供了新的途径和可能. 目前多种干细胞在神经退行性疾病动物模型上的尝试已取得进展. 本文综述了胚胎干细胞、间充质干细胞、神经干细胞等在神经退行性疾病如帕金森氏病、阿尔茨海默氏病、亨廷顿病、肌萎缩性侧索坏死等的治疗中的应用和进展.     

Sirtuins与神经退行性疾病的研究进展

沉默调控基因（SIRTs）是一组激活依赖于NAD＋的具有去乙酰化作用的蛋白。最新的研究表明,SIRTs参与了细胞衰老过程的调节,尤其是在神经退行性疾病中扮演了重要角色。SIRTs基因家族中SIRT2首先发现于酵母中,其余成员则发现于多种有机物中。     

多巴胺与神经退行性疾病研究进展

多巴胺调控人类的情绪和认识能力,包括思想、感觉、理解、推理等,同时,它也在人类的运动功能中发挥重要作用。研究表明多巴胺的合成、储存、释放、降解和重摄取等失衡均与中枢神经系统的多种退行性疾病有密切联系,同时许多治疗疾病的有效药物也围绕多巴胺的研究而产生,如多巴胺替代疗法改善帕金森病的运动症状,多巴胺受体阻断剂可改善舞蹈病的运动症状以及调节多种疾病的精神症状,在临床上都取得了可喜的疗效。然而目前未发现与多巴胺代谢直接相关的基因突变,因此未来需要继续深入研究在神经退行性疾病中造成多巴胺代谢失常的机制,旨在为临床新药物靶点和新治疗手段的研发提供线索。     

TDP-43在神经退行性疾病中的功能和作用

核蛋白TAR DNA/RNA结合蛋43(TDP-43)目前被认为是肌萎缩侧索硬化症(amyotrophic lateral sclerosis,ALS)、额颞叶变性(frontotemporal lobar degeneration,FTLD)等神经退行性疾病的病理学标记蛋白。在中枢神经系统中,TDP-43作为必要的转录调控因子,参与mRNA前体的剪接,维持RNA稳态和运输。在突变和过表达TDP-43的转基因啮齿类动物模型中,受损伤的神经元呈现出胞核和胞质中TDP-43泛素化、磷酸化聚集,以及细胞周期进程的改变。在此,着重阐述基于TDP-43突变或过表达建立神经退行性疾病动物模型的研究进展,探讨其发病机制、病理学改变及治疗方法。     

未折叠蛋白反应在神经退行性疾病中的作用

作为蛋白质分泌途径中蛋白质稳态的主要调节者,未折叠蛋白反应在正常和疾病中都起着至关重要的作用。本文简述了未折叠蛋白反应是否参与神经退行性疾病的发生发展。在许多体外和体内神经退行性病变模型中,未折叠蛋白反应的调节已显示出明显的应用前景。随着未折叠蛋白反应的研究不断深入,还出现了众多靶向未折叠蛋白反应的治疗策略。     

斑马鱼模型在神经退行性疾病研究中的应用进展

随着老龄化社会的进程加快,神经退行性疾病发病率呈现逐年上升趋势。斑马鱼因拥有其他模式动物所不具备的优点,作为模式动物被广泛应用于医学和生命科学的各个研究领域。本文就近年来斑马鱼在常见的神经退行性疾病,如阿尔茨海默病、帕金森病、亨廷顿舞蹈症、肌萎缩侧索硬化、脊髓性肌萎缩、遗传性痉挛性截瘫及其他神经系统相关疾病的研究应用进行综述。     

神经退行性疾病动物模型嗅觉障碍的研究进展

神经退行性疾病是由神经元结构或功能逐渐丧失导致认知及运动障碍的一类不可逆损伤性疾病.其病理改变主要表现为中枢神经的老年斑、神经元纤维缠结、神经元减少等.在神经退行性疾病中,嗅觉障碍通常比经典的运动和认知障碍发生的更早,故将嗅觉障碍作为神经退行性疾病的临床标志有助于此类疾病的早期发现,而其病理过程、发病机制的研究以及治疗...     

小胶质细胞与炎症介导的神经系统退行性病变

小胶质细胞是中枢神经系统常驻细胞,行使支持、营养、免疫监视等多种功能。小胶质细胞在受到感染、外伤等因素刺激后活化,并产生多种免疫效应分子,包括：白细胞介素、肿瘤坏死因子、干扰素γ、活性氮、活性氧等。这些因子介导慢性炎症反应、细胞凋亡等,是导致神经系统退行性病变的主要因素。本文着重阐述小胶质细胞通过分泌这些效应分子引起神经功能损伤的机制,并对目前一些针对性治疗方法加以介绍。     

Stem cells and neurodegenerative diseases

Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the de-velopment of old-aging society, the incidence of neurodegenerative diseases is on the increase. How-ever, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegen-erative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Hunt-ington’s disease and Amyotrophic lateral sclerosis/Lou Gehrig’s disease.     

Glucose,glycolysis, and neurodegenerative diseases

Prolonged survival of a typical postmitotic neuron hinges on a balance between multiple processes, among these are a sustenance of ATP production and protection against reactive oxygen species. In neuropathological conditions, mitochondrial defects often lead to both a drop in ATP levels, as well as increase reactive oxygen species production from inefficient electron transport processes and NADPH-oxidases activities. The former often resulted in the phenomenon of compensatory aerobic glycolysis. The latter stretches the capacity of the cell's redox buffering capacity, and may lead to damages of key enzymes involved in energy metabolism. Several recent reports have indicated that enhancing glucose availability and uptake, as well as increasing glycolytic flux via pharmacological or genetic manipulation of glycolytic enzymes, could be protective in animal models of several major neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis. Activation of canonical Wnt signaling, which improves disease symptoms in mouse models of Alzheimer's disease also appears to work via an elevation of glycolytic enzymes and enhance glucose metabolism. Here, I discuss these findings and the possible underlying mechanisms of how an increase in glucose uptake and glycolysis could be neuroprotective. Increased glycolytic production of ATP would help alleviate energy deficiency, and ATP's hydrotropic effect may enhance solubility and clearance of toxic aggregates prevalent in many neurodegenerative diseases. Furthermore, channeling of glucose into the Pentose Phosphate Pathway would increase the redox buffering capacity of the cell.     

Neuroprotection against neurodegenerative diseases

Neuronal death is directly implicated in the pathogenesis of neurodegenerative diseases (NDDs). NDDs cannot be cured because the mechanisms underlying neuronal death are too complicated to be therapeutically suppressed. Neuroprotective factors, such as neurotrophins, certain growth factors, neurotrophic cytokines, and short neuroprotective peptides, support neuronal survival in both physiological and pathological conditions, suggesting that these factors may be good drug candidates for NDDs. We recently generated a novel neuroprotective peptide named Colivelin by attaching activity-dependent neurotrophic factor (ADNF) to the N-terminus of a potent Humanin derivative, AGA-(C8R)HNG17. HN was originally identified from an Alzheimer’s disease (AD) brain as an endogenous neuroprotective peptide that suppresses AD-relevant toxicity. Colivelin protects neurons from death relevant to NDDs by activating two independent prosurvival signals: an ADNF-mediated Ca²⁺/calmodulin-dependent protein kinase IV pathway and an HN-mediated STAT3 pathway. The neuroprotective effect of Colivelin provides novel insights into therapy for NDDs. An erratum to this article is available at .     

TRPM7 and its role in neurodegenerative diseases

Calcium (Ca²⁺) and magnesium (Mg²⁺) ions have been shown to play an important role in regulating various neuronal functions. In the present review we focus on the emerging role of transient potential melastatin-7 (TRPM7) channel in not only regulating Ca²⁺ and Mg²⁺ homeostasis necessary for biological functions, but also how alterations in TRPM7 function/expression could induce neurodegeneration. Although eight TRPM channels have been identified, the channel properties, mode of activation, and physiological responses of various TRPM channels are quite distinct. Among the known 8 TRPM channels only TRPM6 and TRPM7 channels are highly permeable to both Ca²⁺ and Mg²⁺; however here we will only focus on TRPM7 as unlike TRPM6, TRPM7 channels are abundantly expressed in neuronal cells. Importantly, the discrepancy in TRPM7 channel function and expression leads to various neuronal diseases such as Alzheimer disease (AD) and Parkinson disease (PD). Further, it is emerging as a key factor in anoxic neuronal death and in other neurodegenerative disorders. Thus, by understanding the precise involvement of the TRPM7 channels in different neurodegenerative diseases and by understanding the factors that regulate TRPM7 channels, we could uncover new strategies in the future that could evolve as new drug therapeutic targets for effective treatment of these neurodegenerative diseases.     

TRPM7 and its role in neurodegenerative diseases

Calcium (Ca²⁺) and magnesium (Mg²⁺) ions have been shown to play an important role in regulating various neuronal functions. In the present review we focus on the emerging role of transient potential melastatin-7 (TRPM7) channel in not only regulating Ca²⁺ and Mg²⁺ homeostasis necessary for biological functions, but also how alterations in TRPM7 function/expression could induce neurodegeneration. Although eight TRPM channels have been identified, the channel properties, mode of activation, and physiological responses of various TRPM channels are quite distinct. Among the known 8 TRPM channels only TRPM6 and TRPM7 channels are highly permeable to both Ca²⁺ and Mg²⁺; however here we will only focus on TRPM7 as unlike TRPM6, TRPM7 channels are abundantly expressed in neuronal cells. Importantly, the discrepancy in TRPM7 channel function and expression leads to various neuronal diseases such as Alzheimer disease (AD) and Parkinson disease (PD). Further, it is emerging as a key factor in anoxic neuronal death and in other neurodegenerative disorders. Thus, by understanding the precise involvement of the TRPM7 channels in different neurodegenerative diseases and by understanding the factors that regulate TRPM7 channels, we could uncover new strategies in the future that could evolve as new drug therapeutic targets for effective treatment of these neurodegenerative diseases.     

空气污染与神经退行性疾病

随着现代社会工业的发展,空气污染日益严重,空气污染对人体的损害也越来越大。空气污染中的有害物质,能通过各种途径引起各系统的疾病,甚至会影响儿童的身体和智力发育。研究发现,长期暴露或急性暴露在某些空气污染物中可以直接损伤中枢神经系统,或污染物引起呼吸系统和免疫系统等产生有害因子,通过外周循环到达大脑,导致大脑的神经炎症、神经毒性、氧化应激等反应,最终产生神经退行性病变,如阿尔茨海默病（Alzheimer’s disease,AD）、帕金森病（Parkinson’s disease,PD）等。     

神经炎症与神经退行性疾病的关系

近十多年来的研究表明,在神经退行性疾病的发生与发展中,脑内始终存在着以胶质细胞激活为主要特征的炎症反应。神经炎症是把双刃剑,一方面,它诱发或加重神经系统的退行性病变;另一方面,它在某些特定情况下有利于神经系统损伤的修复。激活的胶质细胞通过释放致炎细胞因子和活性氧自由基等分子介导神经炎症所致的神经元退行性病变,而由调节性T细胞产生的抗炎细胞因子及由神经元释放的抗炎神经肽能保护神经元抵抗神经炎症,从而减缓或减轻神经退行性疾病的进程。     

Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases

Cytoplasmic dynein is the most important molecular motor driving the movement of a wide range of cargoes towards the minus ends of microtubules.As a molecular motor protein,dynein performs a variety of basic cellular functions including organelle transport and centrosome assembly.In the nervous system,dynein has been demonstrated to be responsible for axonal retrograde transport.Many studies have revealed direct or indirect evidence of dynein in neurodegenerative diseases such as amyotrophic lateral sclerosis,Charcot-Marie-Tooth disease,Alzheimer’s disease,Parkinson’s disease and Huntington’s disease.Among them,a number of mutant proteins involved in various neurodegenerative diseases interact with dynein.Axonal transport disruption is presented as a common feature occurring in neurodegenerative diseases.Dynein heavy chain mutant mice also show features of neurodegenerative diseases.Moreover,defects of dynein-dependent processes such as autophagy or clearance of aggregation-prone proteins are found in most of these diseases.Lines of evidence have also shown that dynein is associated with neurodevelopmental diseases.In this review,we focus on dynein involvement in different neurological diseases and discuss potential underlying mechanisms.