胶质细胞与神经元间的信号交流及其与癫痫发病机制的关系

本从胶质细胞与神经元间的信息交流出发,根据国内外研究进展和自已的工作基础,对胶质细胞在癫痫发病机制中的作用进行了分析和论证,对深入研究癫痫的发病机制和防治策略具有指导意义。     

子宫腺肌病发病机制的研究进展

子宫腺肌病是妇科的常见疾病,严重影响妇女的健康和生活质量,其发病机制至今尚未阐明;可能与免疫、血管生成、激素、细胞凋亡、细胞侵袭黏附能力及遗传等因素有关。     

皮肤癣菌病发病机制研究进展

皮肤癣菌病是由皮肤癣菌引起的角化组织感染（皮肤、毛发和甲）,是人群中发病率最高的感染性皮肤病。在皮肤癣菌感染皮肤过程中,蛋白水解酶是皮肤癣菌的主要毒力因子,这种酶需要在合适的pH及温度下才能发挥它的活性而致病;而机体是否被感染则取决于宿主的皮肤机械屏障功能、免疫反应等。     

肠道病毒71型致神经元病变的机制研究进展

中枢神经系统感染是由病原体侵犯中枢神经系统引起的一类具有较高的发病率和死亡率的疾病。病毒是引起中枢神经系统感染的重要病原体之一,其中肠道病毒71型在继发神经系统症状的重症手足口病患儿中较为常见。EV71致神经元病变是其感染中枢神经系统的基础,阐明肠道病毒71型致神经元病变的机制,不仅可以促进基础病毒学研究,也能为抗病毒药物的开发提供思路,对临床肠道病毒71型致中枢神经系统感染的治疗提供支持。本文主要从肠道病毒71型侵入神经元的受体途径、损伤神经元的线粒体途径、诱导凋亡与自噬、感染胶质细胞后对神经元的旁观者效应、免疫病理机制以及病毒自身因素等多个方面,对肠道病毒71型致神经元病变机制展开综述。     

癫痫发作后神经元凋亡的多重调控机制

癫痫是一种慢性脑部疾病。以脑部神经元过度同步化放电所致的突然、反复和短暂的中枢神经系统功能失常为特征。细胞凋亡(apoptosis)是由基因控制的由细胞内部程序激活而发生的自杀性死亡,它在细胞分化、促进体内正常细胞的更新和调节机体发育等方面都起到重要作用。细胞凋亡是癫痫发作后神经元丢失的重要形式。目前认为,癫痫发作后细胞凋亡分子水平的多重调控主要集中在三个方面:(1)细胞凋亡的相关基因及其调控方面;(2)caspase(cysteine proteinases with specificity for aspartic acidresidues,半胱天冬氨酸酶)在细胞凋亡中的作用;(3)线粒体途径在细胞凋亡中的作用。     

癫痫发作后神经元凋亡的多重调控机制

癫痫是一种慢性脑部疾病。以脑部神经元过度同步化放电所致的突然、反复和短暂的中枢神经系统功能失常为特征。细胞凋亡（apoptosis）是由基因控制的由细胞内部程序激活而发生的自杀性死亡,它在细胞分化、促进体内正常细胞的更新和调节机体发育等方面都起到重要作用。细胞凋亡是癫痫发作后神经元丢失的重要形式。目前认为,癫痫发作后细胞凋亡分子水平的多重调控主要集中在三个方面：（1）细胞凋亡的相关基因及其调控方面;（2）caspase（cysteine proteinases with specificity for aspartic acid residues,半胱天冬氨酸酶）在细胞凋亡中的作用;（3）线粒体途径在细胞凋亡中的作用。     

甘丙肽2型受体对氧化应激海马神经元自噬的调控作用及机制研究

本研究旨在解析仔猪脑海马甘丙肽2型受体(galanin receptors type 2,GALR2)参与氧化应激调节的分子机制.本研究基于成功构建的仔猪活体和大鼠海马神经元氧化应激模型,采用实时PCR技术考察仔猪脑海马和大鼠海马神经元GALR2的表达变化.并采用实时PCR、蛋白质印迹法及透射电镜技术进一步探索GALR...     

基于线粒体自噬的特发性肺纤维化发病机制和药物干预的探讨

特发性肺纤维化(idiopathic pulmonary fibrosis, IPF)是一种慢性、进行性且不可逆转的间质性肺疾病,发病机制复杂,预后不良,严重危害公众健康,尚缺乏有效治疗手段。线粒体自噬是一种选择性自噬,可清除损伤或功能异常的线粒体以维持线粒体稳态,其可通过调节氧化应激、肺泡上皮细胞凋亡、肺成纤维细胞活化、上皮-间质转化、炎症反应等病理生理过程对IPF产生重要影响。本文总结线粒体自噬分类及调控机制,重点阐述其在IPF中的作用机制及中西医药物防治研究进展。     

缺血性脑卒中后神经元自噬流障碍的病理机制研究进展

自噬是一个将损伤细胞器、陈旧蛋白、多余胞质组分甚至病原体等通过自噬体呈递给溶酶体进行降解的细胞内代谢过程。它包括自噬启动、自噬体形成、自噬体-溶酶体融合和自噬底物在自噬溶酶体内降解和清除4个步骤。当这些过程呈连续通畅状态则可称为自噬流,自噬/溶酶体信号通路中某一或某些步骤发生阻滞均可导致自噬流障碍。众多研究表明,脑卒中后自噬流障碍是导致脑卒中后缺血半影区神经元损伤的重要原因。本文总结了缺血性脑卒中后神经元自噬流障碍的病理机制研究进展,并介绍了目前改善神经元自噬流障碍方法的研究进展,为深入探究脑卒中病理损伤机制提供参考。     

阿尔采末病发病机制的若干问题

阿乐采末病（ＡＤ）是最常见地老年人致痴呆疾病。约１５％的病人有家族史,其余为散发性。已在第２１、１４及１号染色体发现与家族性ＡＤ有关的突变基因;并在１９号染色体三个等位基因中,发现了同家族性和散发性ＡＤ的遗传易感性都有关的编码载脂蛋白Ｅ的ε－４等位基因。约５０％的散发性病 列以ε－４基因为其致病危险因子。遗传因子和环境因素的相互交织,使ＡＤ的发病机制复杂化,但都以脑内出现β－淀粉样蛋白的沉积和老年     

Juvenile neuronal ceroid lipofuscinosis and education

Juvenile neuronal ceroid lipofuscinosis (JNCL) is characterized by severe visual impairment with onset around age 4–8 years, and a developmental course that includes blindness, epilepsy, speech problems, dementia, motor coordination problems, and emotional reactions. There is presently no cure and the disease leads to premature death. There have been few studies of non-medical intervention for individuals with JNCL, probably because of the negative prognosis. The present chapter discusses the education of children and adolescents with JNCL on the basis of current knowledge about the variation in perceptual, cognitive and language abilities through the course of the disease, and the possibilities that exist for supporting coping and learning within and outside the classroom. Adapted and special needs education may contribute significantly to improved learning conditions, better maintenance of skills and less frustration for individuals with JNCL. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.     

Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis

Juvenile neuronal ceroid lipofuscinosis is caused by mutation of a novel, endosomal/lysosomal membrane protein encoded by CLN3. The observation that the mitochondrial ATPase subunit c protein accumulates in this disease suggests that autophagy, a pathway that regulates mitochondrial turnover, may be disrupted. To test this hypothesis, we examined the autophagic pathway in Cln3(Deltaex7/8) knock-in mice and CbCln3(Deltaex7/8) cerebellar cells, accurate genetic models of juvenile neuronal ceroid lipofuscinosis. In homozygous knock-in mice, we found that the autophagy marker LC3-II was increased, and mammalian target of rapamycin was down-regulated. Moreover, isolated autophagic vacuoles and lysosomes from homozygous knock-in mice were less mature in their ultrastructural morphology than the wild-type organelles, and subunit c accumulated in autophagic vacuoles. Intriguingly, we also observed subunit c accumulation in autophagic vacuoles in normal aging mice. Upon further investigation of the autophagic pathway in homozygous knock-in cerebellar cells, we found that LC3-positive vesicles were altered and overlap of endocytic and lysosomal dyes was reduced when autophagy was stimulated, compared with wildtype cells. Surprisingly, however, stimulation of autophagy did not significantly impact cell survival, but inhibition of autophagy led to cell death. Together these observations suggest that autophagy is disrupted in juvenile neuronal ceroid lipofuscinosis, likely at the level of autophagic vacuolar maturation, and that activation of autophagy may be a prosurvival feedback response in the disease process.     

Chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (Batten disease).

The gene that is involved in juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease--CLN3--has been localized to 16p12, and the mutation shows a strong association with alleles of microsatellite markers D16S298, D16S299, and D16S288. Recently, haplotype analysis of a Batten patient from a consanguineous relationship indicated homozygosity for a D16S298 null allele. PCR analysis with different primers on DNA from the patient and his family suggests the presence of a cytogenetically undetectable deletion, which was confirmed by Southern blot analysis. The microdeletion is embedded in a region containing chromosome 16-specific repeated sequences. However, putative candidates for CLN3, members of the highly homologous sulfotransferase gene family, which are also present in this region in several copies, were not deleted in the patient. If the microdeletion in this patient is responsible for Batten disease, then we conclude that the sulfotransferase genes are probably not involved in JNCL. By use of markers and probes flanking D16S298, the maximum size of the microdeletion was determined to be approximately 29 kb. The microdeletion may affect the CLN3 gene, which is expected to be in close proximity to D16S298.     

Aberrant adhesion impacts early development in a Dictyostelium model for juvenile neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, refers to a group of severe neurodegenerative disorders that primarily affect children. The most common subtype of the disease is caused by loss-of-function mutations in CLN3, which is conserved across model species from yeast to human. The precise function of the CLN3 protein is not known, which has made targeted therapy development challenging. In the social amoeba Dictyostelium discoideum, loss of Cln3 causes aberrant mid-to-late stage multicellular development. In this study, we show that Cln3-deficiency causes aberrant adhesion and aggregation during the early stages of Dictyostelium development. cln3^? cells form ～30% more multicellular aggregates that are comparatively smaller than those formed by wild-type cells. Loss of Cln3 delays aggregation, but has no significant effect on cell speed or cAMP-mediated chemotaxis. The aberrant aggregation of cln3^? cells cannot be corrected by manually pulsing cells with cAMP. Moreover, there are no significant differences between wild-type and cln3^? cells in the expression of genes linked to cAMP chemotaxis (e.g., adenylyl cyclase, acaA; the cAMP receptor, carA; cAMP phosphodiesterase, pdsA; g-protein α 9 subunit, gpaI). However, during this time in development, cln3^? cells show reduced cell-substrate and cell-cell adhesion, which correlate with changes in the levels of the cell adhesion proteins CadA and CsaA. Specifically, loss of Cln3 decreases the intracellular level of CsaA and increases the amount of soluble CadA in conditioned media. Together, these results suggest that the aberrant aggregation of cln3^? cells is due to reduced adhesion during the early stages of development. Revealing the molecular basis underlying this phenotype may provide fresh new insight into CLN3 function.     

Localization of juvenile, but not late-infantile, neuronal ceroid lipofuscinosis on chromosome 16.

The neuronal ceroid lipofuscinoses (NCL) are a group of progressive neurodegenerative disorders characterized by the deposition of autofluorescent proteinaceous fingerprint or curvilinear bodies. We have found that CLN3, the gene underlying the juvenile form of NCL, is very tightly linked to the dinucleotide repeat marker D16S285 on chromosome 16. Integration of D16S285 into the genetic map of chromosome 16 by using the Centre d'Etude du Polymorphisme Humain panel of reference pedigrees yielded a favored marker order in the CLN3 region of qtel-D16S150-.08-D16S285-.04-D16S148-.02-D16S 67-ptel. The most likely location of the disease gene, near D16S285 in the D16S150-D16S148 interval, was favored by odds of greater than 10(4):1 over the adjacent D16S148-D16S67 interval, which was recently reported as the minimum candidate region. Analysis of D16S285 in pedigrees with late-infantile NCL virtually excluded the CLN3 region, suggesting that these two forms of NCL are genetically distinct.     

Microglia in juvenile neuronal ceroid lipofuscinosis are primed toward a pro‐inflammatory phenotype

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. Regions of microglial activation precede and predict areas of neuronal loss in JNCL; however, the functional role of activated microglia remains to be defined. The inflammasome is a key molecular pathway for activating pro‐IL‐1β in microglia, and IL‐1β is elevated in the brains of JNCL patients and can induce neuronal cell death. Here, we utilized primary microglia isolated from CLN3^Δex7/8 mutant and wild‐type (WT) mice to examine the impact of CLN3 mutation on microglial activation and inflammasome function. Treatment with neuronal lysates and ceramide, a lipid intermediate elevated in the JNCL brain, led to inflammasome activation and IL‐1β release in CLN3^Δex7/8 microglia but not WT cells, as well as increased expression of additional pro‐inflammatory mediators. Similar effects were observed following either TNF‐α or IL‐1β treatment, suggesting that CLN3^Δex7/8 microglia exist in primed state and hyper‐respond to several inflammatory stimuli compared to WT cells. CLN3^Δex7/8 microglia displayed constitutive caspase‐1 activity that when blocked led to increased glutamate release that coincided with hemichannel opening. Conditioned medium from activated CLN3^Δex7/8 or WT microglia induced significant cell death in CLN3^Δex7/8 but not WT neurons, demonstrating that intrinsically diseased CLN3^Δex7/8 neurons are less equipped to withstand cytotoxic insults generated by activated microglia. Collectively, aberrant microglial activation may contribute to the pathological chain of events leading to neurodegeneration during later stages of JNCL.