伴侣蛋白Mortalin与神经退行性疾病的研究进展

1993年,Wadhwa等[1]在小鼠胚胎成纤维细胞(mouse embryonic fibroblasts, MEF)中首次克隆出了Mortalin(mtHSP70/HSP75/Grp75/TRAP-1/PBP74),它是热休克蛋白70(heat-shock protein 70, HSP70)家族成员之一.研究表明,Mortalin参与了多种生理功能的调控,包括细胞存活、细胞增殖、压力应激、线粒体合成、细胞内转运等,并且可能在神经系统疾病中发挥作用.在此,本文就Mortalin的基本结构、生理功能以及与神经系统疾病尤其是神经退行性疾病的相关性作一个综述.     

胰岛素抵抗在神经退行性疾病中的作用*

Insulin resistance is a condition in which the cells fail to respond to the normal actions of insulin, acting as decreased glucose utilization, abnormal glucose tolerance and compensatory increased insulin concentration in the serum. Altered insulin-related indicator has been detected in neurodegenerative diseases. Recent studies indicate that insulin resistance is involved in the occurrence and development of neurodegenerative diseases, including Alzheimers disease, Parkinsons disease, Huntingtons disease, etc. This review summarizes the relationship between insulin resistance and neurodegenerative diseases.     

人类神经退行性疾病的果蝇研究模型

大脑特定区域的迟发性细胞丢失和神经解剖学及行为学上的异常是人类神经退行性疾病 (humannuerodegenerativedisorder,HND)的典型特征。最近的研究表明 ,以果蝇为实验对象进行的分子遗传学研究对阐明这些疾病的可能致病机理能够提供新的重要线索。     

褪黑素在神经退行性疾病中的应用

神经退行性疾病是一类由急慢性病理因素所引发的, 以神经细胞变性, 丢失、 退化为主要病理 特征的中枢神经系统功能衰退性疾病。 它是第二大类常见的死亡原因, 预防神经退行性疾病已成为一个新 兴的公共卫生领域, 对我们社会造成了巨大的挑战。 褪黑素是松果体激素, 具有多种生理功能, 主要包括 调节昼夜节律, 清除自由基, 抑制生物分子氧化, 抑制神经炎症。 神经退行性疾病患者褪黑素的水平降低, 褪黑素通过调节病理生理机制和信号通路发挥神经保护作用, 提示褪黑素有可能成为新的治疗药物。     

丝氨酸蛋白酶抑制因子serpins在神经退行性疾病中作用的研究进展

丝氨酸蛋白酶抑制因子(serpins)是一类丝氨酸蛋白酶活性调节剂,可控制炎症因子表达,对补体系统、凝血与免疫反应过程中的蛋白酶具有抑制作用。Serpin家族可在中枢神经系统中表达,参与胚胎发育过程中的轴突发生和突触发生,以及成年突触可塑性和情绪行为控制等生理过程。常见的神经退行性疾病包含帕金森病(PD)、阿尔茨海默病(AD)、肌萎缩侧索硬化(ALS)、亨廷顿病(HD)。本文综述了serpins的基因表达和抑制作用,及其与PD、AD、ALS、HD神经退行性疾病进展的关系。Serpins参与了多种神经退行性疾病进程,靶向调控serpins有望成为治疗神经退行性疾病的一种新策略。     

硫化氢对神经退行性疾病保护作用的研究进展

硫化氢(hydrogen sulfide,H2S)一直被认为是一种有毒气体.近年来,越来越多的研究显示H2S在哺乳动物体内可以调节及参与一定范围的生理和病理过程.H2S在中枢神经系统中扮演着重要的角色.H2S具有抗氧化应激、抗凋亡以及抗炎的作用,而这些生理学意义对研究防治包括阿尔茨海默病、帕金森氏病在内的神经退行性疾病有着重要的启示.     

干细胞治疗神经退行性疾病的前景与问题干细胞治疗神经退行性疾病的前景与问题

背景：虽然各种神经退行性疾病的人群发病率居高不下且有上升趋势,但至今仍无有效治疗方法,因此,寻求有效的治疗神经退行性疾病的途径是科学界面临的挑战。 目的：文章分析和综述了对干细胞治疗神经退行性疾病的近年研究进展及热点问题。 方法：文章对干细胞移植治疗神经退行性疾病,如阿尔茨海默病、帕金森病、脑卒中、亨廷顿病、视网膜色素变性疾病、肌萎缩性侧索硬化症、癫痫等疾病的基础与临床研究进展进行概述,探讨干细胞治疗神经退行性疾病的可行性、优势及问题。 结果与结论：干细胞治疗神经退行性疾病大部分研究还是集中在实验动物模型阶段,还没有支持干细胞临床治疗的有效证据,其安全性和有效性还没有确切临床保证和标准,临床治疗效果及不良反应都有待大宗及长期临床试验研究进一步验证。     

脑老化与神经系统退变性疾病

一般认为正常人或健康的脑老化现象，脑的结构与功能已发生病变，与出现以个体行为和认知能力等异常为基本临床表现的神经系统退变性疾病是两个相互独立现象。但是，已有许多证据表明，二者具有相互重叠的临床和神经病理特征、相似的生化改变和病因与发病机制。因此，现在有人认为，脑老化可能是神经系统退变性疾病的最初级阶段，与疾病的发生有着相同的基础。对它的认识，可为神经系统退变性疾病的治疗提出新的思路。本文拟对此作一介绍。     

Casein kinase 1 delta is associated with pathological accumulation of tau in several neurodegenerative diseases

The distribution of casein kinase 1 delta (Cki delta) was studied by immunohistochemistry and correlated with other pathological hallmarks in Alzheimer's disease (AD), Down syndrome (DS), progressive supranuclear palsy (PSP), parkinsonism dementia complex of Guam (PDC), Pick's disease (PiD), pallido-ponto-nigral degeneration (PPND), Parkinson's disease (PD), dementia with Lewy bodies (DLB), amyotrophic lateral sclerosis (ALS), and elderly controls. Cki delta was found to be associated generally with granulovacuolar bodies and tau-containing neurofibrillary tangles in AD, DS, PSP, PDC, PPND, and controls, and Pick bodies and ballooned neurons in PiD. It was not associated with tau-containing inclusions in astroglia and oligodendroglia in PPND, PSP, and PDC. It was also not associated with tau-negative Lewy bodies in PD and DLB, Hirano bodies in PDC, Marinesco bodies in PD, AD, and controls and "skein"-like inclusions in anterior motor neurons in ALS. The colocalization of the kinase Cki delta and its apparent substrate tau suggests a function for Cki delta in the abnormal processing of tau.     

Association of micronucleus frequency with neurodegenerative diseases

Micronuclei (MNi) can originate either from chromosome breakage or chromosome malsegregation events and are therefore ideal biomarkers to investigate genomic instability. Studies in peripheral lymphocytes of patients with neurodegenerative diseases, mainly Alzheimer's disease (AD) and Parkinson's disease (PD), revealed an increased micronucleus (MN) frequency in both disorders but originating mainly from chromosome malsegregation events in AD and from chromosome breakage events in PD. Studies in other neurodegenerative diseases are largely missing, and some data in premature ageing disorders characterised by neurodegeneration and/or neurological complications, such as Ataxia telangiectasia, Werner's syndrome, Down's syndrome (DS) and Cockayne's syndrome, indicate that MNi increase with ageing in cultured cells. An increased frequency of aneuploidy characterises several tissues of AD patients, as well as of individuals at increased risk to develop AD, such as mothers of DS individuals and DS subjects themselves. The use of the buccal MN cytome assay in AD and DS subjects allowed finding significant changes in the MN frequency as well as other cellular modifications reflecting reduced regenerative capacity compared to age- and gender-matched controls. These changes in buccal cytome ratios may prove useful as potential future diagnostics to identify individuals of increased risk for these disorders.     

Inflammation in neurodegenerative diseases

Summary Neurodegeneration, the slow and progressive dysfunction and loss of neurons and axons in the central nervous system, is the primary pathological feature of acute and chronic neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury and multiple sclerosis. Despite different triggering events, a common feature is chronic immune activation, in particular of microglia, the resident macrophages of the central nervous system. Apart from the pathogenic role of immune responses, emerging evidence indicates that immune responses are also critical for neuroregeneration. Here, we review the impact of innate and adaptive immune responses on the central nervous system in autoimmune, viral and other neurodegenerative disorders, and discuss their contribution to either damage or repair. We also discuss potential therapies aimed at the immune responses within the central nervous system. A better understanding of the interaction between the immune and nervous systems will be crucial to either target pathogenic responses, or augment the beneficial effects of immune responses as a strategy to intervene in chronic neurodegenerative diseases.     

Brain drug delivery and neurodegenerative diseases: Polymeric PLGA-based nanoparticles as a forefront platform

The discovery of effective drugs for the treatment of neurodegenerative disorders (NDs) is a deadlock. Due to their complex etiology and high heterogeneity, progresses in the development of novel NDs therapies have been slow, raising social/economic and medical concerns. Nanotechnology and nanomedicine evolved exponentially in recent years and presented a panoply of tools projected to improve diagnosis and treatment. Drug-loaded nanosystems, particularly nanoparticles (NPs), were successfully used to address numerous drug glitches, such as efficacy, bioavailability and safety. Polymeric nanoparticles (PNPs), mainly based on polylactic-co-glycolic acid (PLGA), have been already validated and approved for the treatment of cancer, neurologic dysfunctions and hormonal-related diseases. Despite promising no PNPs-based therapy for neurodegenerative disorders is available up to date. To stimulate the research in the area the studies performed so far with polylactic-co-glycolic acid (PLGA) nanoparticles as well as the techniques aimed to improve PNPs BBB permeability and drug targeting were revised. Bearing in mind NDs pharmacological therapy landscape huge efforts must be done in finding new therapeutic solutions along with the translation of the most promising results to the clinic, which hopefully will converge in the development of effective drugs in a foreseeable future.     

The cytoskeleton in neurodegenerative diseases

Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases that are broadly classified by filamentous aggregates of neuronal intermediate filament (IF) proteins, or by inclusions containing the microtubule-associated protein (MAP) tau. The discovery of mutations in neuronal IF and tau genes firmly establishes the importance of neuronal IF proteins and tau in the pathogenesis of neurodegenerative diseases. Multiple IF gene mutations are pathogenic for Charcot-Marie-Tooth (CMT) disease and amyotrophic lateral sclerosis (ALS)--in addition to those in the copper/zinc superoxide dismutase-1 (SOD1) gene. Tau gene mutations are pathogenic for frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and tau polymorphisms are genetic risk factors for sporadic progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Thus, IF and tau abnormalities are linked directly to the aetiology and pathogenesis of neurodegenerative diseases. In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case. As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.     

Biomarker-based dissection of neurodegenerative diseases

The diagnosis of neurodegenerative diseases within neurology and psychiatry are hampered by the difficulty in getting biopsies and thereby validating the diagnosis by pathological findings. Biomarkers for other types of disease have been readily adopted into the clinical practice where for instance troponins are standard tests when myocardial infarction is suspected. However, the use of biomarkers for neurodegeneration has not been fully incorporated into the clinical routine. With the development of cerebrospinal fluid (CSF) biomarkers that reflect pathological events within the central nervous system (CNS), important clinical diagnostic tools are becoming available. This review summarizes the most promising biomarker candidates that may be used to monitor different types of neurodegeneration and protein inclusions, as well as different types of metabolic changes, in living patients in relation to the clinical phenotype and disease progression over time. Our aim is to provide the reader with an updated lexicon on currently available biomarker candidates, how far they have come in development and how well they reflect pathogenic processes in different neurodegenerative diseases. Biomarkers for specific pathogenetic processes would also be valuable tools both to study disease pathogenesis directly in patients and to identify and monitor the effect of novel treatment strategies.     

神经营养因子与神经元退行性变疾病

神经元退行性变疾病包括多种疾病,如常见的老年性痴呆（alzheimer’s disease,AD）和帕金森病（parkinson disease,PD）等。此类疾病的共同特点是进行性的神经元损伤。由于发病机制复杂,并涉及许多至今未知的因素,目前尚无有效的干预措施,故阐明神经元退行性变疾病的发生机制十分重要。神经营养因子（neurotrophic factors,NTFs）是一类调节神经系统发育、成熟和维持神经元功能的天然蛋白质,在神经系统的发生、发育、营养、存活及损伤后修复中起重要作用,是神经元存活和发挥功能的基础。因此,本文主要讨论NTFs与神经元退行性变疾病特别是AD和PD之间的关系。