Rho/ROCK信号通路与神经系统疾病

Rho/ROCK是机体各组织中普遍存在的一条信号转导通路,介导的信号通路参与细胞的收缩、黏附、迁移、增殖、细胞骨架的形成等多种细胞生物学行为和功能[1-2]。目前越来越多的证据表明,Rho/ROCK在神经系统疾病的发生发展中具有重要作用,对Rho/ROCK信号通路的研究将为某些神经系统疾病的诊断治疗提供新的思路。     

Rho/ROCK信号通路与中枢神经轴突再生

Rho是GTP酶Rho家族中调节肌动蛋白细胞骨架最具特征的成员之一,其最经典的下游底物是Rho激酶(ROCK)。最新研究表明,Rho/ROCK信号通路除了参与缺血性卒中血流动力学障碍及炎症反应以外,还可直接作用于神经元,从而直接导致生长锥塌陷及神经突起回缩。Rho/ROCK信号通路的抑制能够促进中枢神经系统受损后轴突的再生和功能的恢复。目前,ROCK抑制剂之一盐酸法舒地尔(Fasudil)已应用于临床,尤其是在脑血管疾病的治疗中具有广阔的应用前景。     

谷氨酸转运蛋白与神经系统疾病

脑组织具有明显收集谷氨酸的能力,而转运蛋白是使谷氨酸从细胞外液有效地被转走的唯一功能单位,也是长期维持谷氨酸在细胞外低浓度和无毒性的重要因素。谷氨酸转运蛋白在调节神经传导方面似乎也有着较复杂的功能,它们调节突触间的时程,突触外间隙与邻近突触之间受体激活和失活的程度及方式,同时也为γ-氨基丁酸,谷胱甘肽和蛋白质的合成及能量的产生提供谷氨酸。像谷氨酸一样,谷氨酸转运蛋白与谷氨酸有关的突触的正常功能的维持和某些神经系统疾病(如脑缺血,肌萎缩性侧索硬化,阿尔茨海默病,创伤性脑损伤及癫痫等)相关。     

金属硫蛋白与神经系统疾病

195 7年 Margoshes和 Vallee在马的肾皮质中首先发现了金属硫蛋白(MT)。随后的研究证实 MT是一种广泛存在于细菌、真菌、植物和真核生物中的高度保守的细胞内蛋白质 ,具广泛的生物学特性 ,如参与金属离子 Cu2 、Zn2 的稳态的维持 ,抗氧自由基损伤和参与调节谷氨酸能和 γ-氨     

RhoA/Rho激酶信号通路对小鼠抗衰老Klotho蛋白表达的影响

目的观测RhoA/ROCK信号通路对小鼠脑脉络丛Klotho(KL)蛋白表达的影响。方法将24只昆明小鼠随机分为3组,即对照组,一氧化氮合酶(Nitric Oxide Synthesis,NOS)抑制组(L-NAME组)和L-NAME+法舒地尔组,连续处理4周。用免疫组织化学方法观察KL蛋白表达;Western blot检测KL蛋白表达水平的变化;RT-PCR检测RhoA和ROCK mRNA表达水平。结果与对照组比较,L-NAME组ROCK mRNA表达水平升高(P0.01),KL蛋白表达水平明显降低(P0.01)。给予ROCK阻滞剂法舒地尔后ROCK mRNA表达水平降低(P0.01),Kl蛋白表达水平明显增高(P0.01)。结论L-NAME所致KL蛋白表达下调与RhoA/ROCK信号通路活性增强有关。     

X-连锁凋亡抑制蛋白通路与神经系统疾病

X-连锁凋亡抑制蛋白(XIAP)是重要的内源性凋亡抑制因子,通过抑制不同的半胱天冬酶等多种途径而发挥抗凋亡作用.许多神经系统疾病的发生与发展涉及细胞凋亡机制,XIAP在细胞凋亡机制中扮演着一个重要角色.     

Notch信号通路与神经系统疾病

Notch信号通路存在于多种动物体内,是许多重要细胞信号转导通路的交汇点,在胚胎发育中对细胞的命运决定起关键作用.Notch信号转导紊乱将导致很多神经系统疾病的发生.本文对Notch信号通路组成、功能、与神经系统发育和某些疾病的关系进行综述.     

Rho/Rho激酶与蛛网膜下腔出血后脑血管痉挛

脑血管痉挛是蛛网膜下腔出血最严重的并发症之一，其发病机制尚不十分清楚。近年来，Rbo/Rbo激酶通路在蛛网膜下腔出血后脑血管痉挛中的作用受到越来越多的关注。Rbo／Rho激酶通路通过多种机制影响脑血管痉挛的发生和发展。选择性Rbo激酶抑制剂对脑血管痉挛的有益作用也已在动物实验和临床研究中得到证实。文章综述了Rbo／Rho激酶通路的作用机制及其在脑血管痉挛治疗方面的作用。     

Notch信号通路在神经系统疾病中的研究进展

Notch信号通路调节发育中的多个细胞过程,尤其在神经系统的生长发育中起着重要作用,如调控胶质细胞再生、神经发生、神经突起形成等。因此,Notch信号的异常将导致多种神经系统疾病。本文就Notch信号通路的结构、功能、调节神经系统发育及所致神经系统疾病进行综述。     

热休克蛋白60在神经系统疾病作用的研究进展

热休克蛋白60(HSP60)是热休克蛋白家族中的最重要成员之一,是一种高度保守伴侣蛋白,除扮演分子伴侣的功能,参与线粒体质量控制体系外,还具有促凋亡和抗凋亡双作用并参与炎症、免疫等生物学功能,与神经系统疾病的发生、发展密切相关。本文从HSP60的结构、功能及在神经系统疾病的研究进展进行综述。     

Rho/ROCK pathway as a target of tumor therapy

This study emphasizes the importance of Rho/ROCK pathway in lovastatin-induced apoptosis as replenishment with exogenous isoprenoid, geranylgeranylpyrophosphate (GGPP), resulted in inhibition of apoptosis in cultured tumor cells. Treatment of C6 glioma cells with Toxin B and exoenzyme C3 resulted in cell death suggesting the role of geranylgeranylated protein(s) in the survival of glioma cells. Relative apoptotic death observed in cells transfected with dominant negative constructs of RhoA, Rac, and cdc42 imply Rho A as playing the major role in cell survival. Furthermore, the inhibition of Rho A kinase (ROCK), a direct downstream effector of Rho A, by Y-27632 or dominant negative of ROCK, induced apoptosis in glioma cells. These findings indicate that RhoA/ROCK pathway is involved negatively in the regulation of glioma cell death pathway. Moreover, in vivo studies of lovastatin treatment in animals implanted with C6 glioma cell tumors also resulted in smaller tumor size and induced apoptosis in the tumor tissue. The implantation of stably transfected C6 glioma cells with expression vector of C3 exoenzyme, dominant negative of RhoA and ROCK, resulted in significant smaller tumor mass, further establishing the importance of geranylgeranylated proteins, specifically RhoA and its downstream effecter ROCK, in cell survival and tumor genesis.     

The role of the Rho/ROCK signaling pathway in inhibiting axonal regeneration in the central nervous system

The Rho/Rho-associated coiled-coil containing protein kinase (Rho/ROCK) pathway is a major signaling pathway in the central nervous system, transducing inhibitory signals to block regeneration. After central nervous system damage, the main cause of impaired regeneration is the presence of factors that strongly inhibit regeneration in the surrounding microenvironment. These factors signal through the Rho/ROCK signaling pathway to inhibit regeneration. Therefore, a thorough understanding of the Rho/ROCK signaling pathway is crucial for advancing studies on regeneration and repair of the injured central nervous system.     

Inhibition of the Rho/ROCK pathway reduces apoptosis during transplantation of embryonic stem cell-derived neural precursors

Rho-GTPase has been implicated in the apoptosis of many cell types, including neurons, but the mechanism by which it acts is not fully understood. Here, we investigate the roles of Rho and ROCK in apoptosis during transplantation of embryonic stem cell-derived neural precursor cells. We find that dissociation of neural precursors activates Rho and induces apoptosis. Treatment with the Rho inhibitor C3 exoenzyme and/or the ROCK inhibitor Y-27632 decreases the amount of dissociation-induced apoptosis (anoikis) by 20-30%. Membrane blebbing, which is an early morphological sign of apoptosis; cleavage of caspase-3; and release of cytochrome c from the mitochondria are also reduced by ROCK inhibition. These results suggest that dissociation of neural precursor cells elicits an intrinsic pathway of cell death that is at least partially mediated through the Rho/ROCK pathway. Moreover, in an animal transplantation model, inhibition of Rho and/or ROCK suppresses acute apoptosis of grafted cells. After transplantation, tumor necrosis factor-alpha and pro-nerve growth factor are strongly expressed around the graft. ROCK inhibition also suppresses apoptosis enhanced by these inflammatory cytokines. Taken together, these results indicate that inhibition of Rho/ROCK signaling may improve survival of grafted cells in cell replacement therapy.     

S1P inhibits gap junctions in astrocytes: involvement of G and Rho GTPase/ROCK

Sphingosine-1-phosphate (S1P) is a potent and pleiotropic bioactive lysophospholipid mostly released by activated platelets that acts on its target cells through its own G protein-coupled receptors. We have previously reported that mouse striatal astrocytes expressed mRNAs for S1P1 and S1P3 receptors and proliferate in response to S1P. Here, we investigated the effect of S1P on gap junctions. We show that a short-term exposure of astrocytes to S1P causes a robust inhibition of gap junctional communication, as demonstrated by dye coupling experiments and double voltage-clamp recordings of junctional currents. The inhibitory effect of S1P on dye coupling involves the activation of both Gi and Rho GTPases. Rho-associated kinase (ROCK) also plays a critical role. The capacity of S1P to activate a Rho/ROCK axis in astrocytes is demonstrated by the typical remodeling of actin cytoskeleton. Connexin43, the protein forming gap junction channels, is a target of the Gi- and Rho/ROCK-mediated signaling cascades. Indeed, as shown by Western blots and confocal immunofluorescence, its nonphosphorylated form increases following S1P treatment and this change does not occur when both cascades are disrupted. This novel effect of S1P may have an important physiopathological significance when considering the proposed roles for astrocyte gap junctions on neuronal survival.     

Actin-binding Rho activating protein is expressed in the central nervous system of normal adult rats

Previous studies show that actin-binding Rho activating protein (Abra) is expressed in cardiomyocytes and vascular smooth muscle cells.In this study,we investigated the expression profile of Abra in the central nervous system of normal adult rats by confocal immunofluorescence.Results showed that Abra immunostaining was located in neuronal nuclei,cytoplasm and processes in the central nervous system,with the strongest staining in the nuclei;in the cerebral cortex,Abra positive neuronal bodies and processes were distributed in six cortical layers including molecular layer,external granular layer,external pyramidal layer,internal granular layer,internal pyramidal layer and polymorphic layer;in the hippocampus,the cell bodies of Abra positive neurons were distributed evenly in pyramidal layer and granular layer,with positive processes in molecular layer and orien layer;in the cerebellar cortex,Abra staining showed the positive neuronal cell bodies in Purkinje cell layer and granular layer and positive processes in molecular layer;in the spinal cord,Abra-immunopositive products covered the whole gray matter and white matter;co-localization studies showed that Abra was co-stained with F-actin in neuronal cytoplasm and processes,but weakly in the nuclei.In addition,in the hippocampus,Abra was co-stained with F-actin only in neuronal processes,but not in the cell body.This study for the first time presents a comprehensive overview of Abra expression in the central nervous system,providing insights for further investigating the role of Abra in the mature central nervous system.     

Rac/Rho pathway regulates actin depolymerization induced by aminoglycoside antibiotics

Stress stimuli can lead to remodeling of the actin cytoskeleton and subsequent alteration of cell adhesion and permeation as well as cell functions and cell fate. We investigated redox-dependent Rho GTPase-linked pathways controlling the actin cytoskeleton in the inner ear of the CBA mouse, by using aminoglycoside antibiotics as a noxious stimulus that causes loss of sensory cells via the formation of reactive oxygen species. Kanamycin treatment in vivo interfered with the formation of F-actin, disturbed the arrangement of beta-actin in the stereocilia of outer hair cells, and altered the intermittent adherens junction/tight junction complexes between outer hair cells and supporting cells. The drug treatment also activated Rac1 and promoted the formation of the complex of Rac1 and p67phox while decreasing the activity of RhoA and reducing the formation of the RhoA/p140mDia complex. In inner-ear-derived cell lines, expression of mutated Rac1 changed the structural arrangement of F-actin and diminished the immunoreactivity of p140mDia. These findings suggest that actin depolymerization induced by kanamycin is mediated by Rac1 activation, followed by the formation of superoxide by NADPH oxidase. These changes will ultimately contribute to aminoglycoside-induced loss of hair cells.     

Purkinje cell survival in organotypic cultures: implication of Rho and its downstream effector ROCK

Organotypic cultures of postnatal day 1 (P1) to P7 mouse cerebella are well-established models for studying cell survival. In the present work, we investigate the involvement of the Rho/ROCK intracellular pathway in Purkinje cell survival by using organotypic cultures of P3 Swiss mice. Specific inhibitors of Rho or ROCK were applied at different concentrations to the slice cultures, which were maintained for 5 days in vitro. We show that the bacterial exoenzyme C3 transferase, a specific inhibitor of the small GTPase Rho, increases Purkinje cell survival. There is a 4.5- and 2.5-fold increase in Purkinje cell survival when C3 intracellular uptake is promoted either by the PEP-1 peptide or by the C2IN carrier protein, respectively, and not with the commonly used TAT peptide. Moreover, treatment with Y27632 and H-1152, two specific inhibitors of the Rho kinase ROCK, also strongly reduces apoptotic cell death and results in 6.5- and 8.5-fold increases in cell survival, respectively. In immunohistochemical analysis, we also show that H-1152 did not change either glial fibrillary acidic protein or isolectin-B4 staining, indicating that this compound did not alter the cellular composition in our cultures. Thus, our data demonstrate that inhibition of Rho and its downstream effector ROCK may be used to enhance cell survival in neurodegenerative diseases.     

Small Rho GTPases are key regulators of peripheral nerve biology in health and disease

A thorough knowledge of the cellular and molecular basis of the structure and function of peripheral nerves is of paramount importance not only for a better understanding of the fascinating biology of the peripheral nervous system but also for providing critical insights into the various diseases affecting peripheral nerves as the firm foundation of potential treatments. Genetic approaches in model organisms, in combination with research on hereditary forms of neuropathies, have contributed significantly to our progress in this field. In this review, we will focus on recent advances using these synergistic approaches that led to the identification of small Rho GTPases and their regulators as crucial functional players in proper development and function of myelinated peripheral nerves, with a particular emphasis on the cell biology of Schwann cells in health and disease.     

Motor protein diseases of the nervous system.

Motor proteins link concepts of impaired axonal transport with concepts of impaired energy metabolism in motor neuron disease. Thus it is not surprising that in recent years several reports on the relevance of motor protein function in mice models for motor neuron disease as well as motor neuron patients have appeared. This article summarizes the broad spectrum of neurological phenotypes, which are caused by alterations of motor protein function. This is likely to add to the understanding of motor neuron disease and may be relevant in terms of future therapeutic approaches.