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。     

血红素氧合酶及其在神经系统疾病中的作用

血红素氧合酶(heme oxygenase,HO)是生物体内血红素降解的催化酶,它催化血红素降解为等摩尔的胆绿素、一氧化碳(carbonmonoxide,CO)和铁.近年来发现它除了具有降解血红素的功能外,还在许多生理和病理过程中起重要的作用,与神经系统疾病如脑血管病、脊髓病变、帕金森病、阿尔茨海默病等亦有很大关系,故如何从药理学水平、分子水平及基因水平调节HO的表达,并应用到神经系统疾病的研究或临床.     

脑血管病神经系统并发症的诊断与处理

本文对脑血管疾病常见的吞咽障碍、偏瘫肩痛、癫(癎)、卒中后抑郁、认知功能障碍等神经系统并发症的发病机制、诊断与处理进行综述,以改善患者的预后.     

磁共振弥散张量成像技术在老年神经系统疾病的应用

弥散张量成像技术(DTI)是一种新的磁共振成像技术,是目前在活体上无创定量测量脑白质纤维完整性的唯一方法。近年来,DTI技术也越来越多地被应用于老年神经系统疾病的研究中,如痴呆与认知功能损害、帕金森病、脑血管疾病、老年期抑郁等。本文就DTI技术在老年神经系统疾病的应用作一综述。     

神经系统钙离子通道病

钙通道广泛分布于不同类型的组织细胞中,其在神经系统中的作用尤为重要。钙通道功能障碍可以引起 多种神经系统疾病,本文对钙通道的结构、功能及钙通道障碍引起的神经系统疾病进行了综述。     

天然反义转录物在神经系统疾病发病机制中的作用

天然反义转录物(NATs)在生物体内普遍存在。人们逐渐认识到NATs具有重要作用,能够调控基因表达。NATs在哺乳动物神经系统尤为普遍,其对神经系统正常生理功能有重要调节作用。NATs不仅参与神经元分化、髓鞘形成和离子通道调控,还参与突触可塑性和学习记忆等高级认知功能。本文重点讨论NATs在神经系统疾病尤其是神经变性病发病机制中的作用。     

血红素加氧酶系统在神经系统疾病中变化的研究进展

血红素加氧酶(HO)在神经系统广泛分布,其反应产物即铁离子、一氧化碳和胆色素都是生物活性分子,对细胞的生存和增殖有广泛的生物学作用。同工酶HO-1和HO-2不同的分子特性和脑内不同的调控特点决定了两者神经功能的差别。HO-2在生理情况下大量表达维持脑的正常功能;而HO-1与神经系统疾病密切相关。大量研究表明HO-1的上调表达对氧化应激引起的神经系统疾病有保护作用,另一方面使铁离子病理性沉积促进了神经系统变性疾病的发生。     

自噬与神经系统疾病研究进展

自噬是细胞内降解/再循环系统,被称为II型程序性细胞死亡。近年来研究表明自噬广泛参与神经系统发育以及脑缺血、痴呆、帕金森病等神经系统重大疾病的发生与发展,但在自噬对神经细胞死亡的作用上还存在较大争议。本文就自噬与神经系统疾病的关系研究进展加以综述,从而有助于今后深入探索自噬在神经系统疾病中的功能并开辟神经系统疾病新的治疗方向。     

MicroRNA-34a在神经系统疾病中的研究进展

microRNA是一类具有调控功能的非编码RNA;microRNA-34a(miR-34a)是其中的一种,已经证实其在脑组织中广泛表达。最新研究表明,miR-34a通过调控相应蛋白的表达,调节脑组织中细胞的增殖、分化和凋亡,从而广泛地参与到神经系统各类疾病如神经系统肿瘤、神经损伤、神经变性疾病等的发生、发展及修复过程,发挥其独特的调控作用。本文就miR-34a在神经系统各类疾病的病理生理过程中的作用及相关机制做一简要综述。     

PET在中枢神经系统疾病中的研究与应用

本文述及了脑受体显像剂的种类,在脑功能研究方面及神经系统主要疾病中的研究、应用。从分子水平认识脑的功能及神经系统疾病发生、发展的病理生理过程,从而阐明了在神经系统疾病诊断、鉴别诊断中的临床价值。     

Synucleinopathies: a pathological and molecular review

Synucleins are a family of small, presynaptic neuronal proteins comprised of α-, β-, γ-synucleins and synoretin, of which only α-synuclein aggregates have been associated with several neurological diseases. The normal neuronal function of synucleins are presently unknown, but several activities such as lipid vesicle binding, inhibition of phospholipase D2 and protein kinase C, dopamine uptake and as a chaperone have been ascribed to α-synuclein. The role of synuclein in the etiology of neuropathology has developed from several observations. Pathologically, synuclein was identified as the major component of Lewy bodies (LBs), the hallmark inclusions of Parkinson's disease (PD), and a fragment thereof was isolated from amyloid plaques of a different neurological disease, Alzheimer's disease (AD). Biochemically, recombinant α-synuclein was shown to be able to form fibrils which recapitulated the ultrastructural features of α-synuclein isolated from patients with dementia with LBs (DLB), PD and multiple system atrophy (MSA). Additionally, the identification of mutations within the synuclein gene, albeit in rare cases of familial PD, demonstrated an unequivocal link between synuclein pathology and neurodegenerative disease. The common involvement of α-synuclein in a spectrum of diseases such as PD, DLB, MSA and the LB variant of AD has led to the classification of these diseases under the umbrella term of synucleinopathies.     

细胞凋亡在脊髓小脑性共济失调3型发病机制中的作用

目的研究细胞凋亡在脊髓小脑性共济失调3型(SCA3)分子发病机制中的作用。方法将带有SCA3正常与突变基因的增强型绿色荧光蛋白真核表达载体(pEGFP)转染大鼠肾上腺嗜铬细胞瘤(PC12)细胞,采用丫啶橙(AO)染色及电镜观察细胞凋亡的发生情况,免疫荧光检测转染后24h、72h、120h半胱氨酸天门冬氨酸酶3、8(caspase3、8)在细胞核内的分布及其与核内包涵体(INIs)共定位的情况;缺口末端标记(TUNEL)法观察正常基因组与突变基因组以及突变基因组在给予广谱caspase阻断剂zVAD-fmk(100μmol/L)后细胞凋亡的变化。结果随着转染后时间的延长,突变基因组细胞发生了明显的凋亡,caspase3、caspase8核内与INIs共定位。正常组与突变组TUNEL阳性细胞数有明显差异并有显著性意义(P<0.01),突变组在给予zVAD-fmk后细胞凋亡明显减轻,差异有显著性意义(P<0.01)。结论细胞凋亡在SCA3发病机制中起重要的作用,抑制凋亡通路可以减少细胞死亡,推测对凋亡环节的干预有可能成为SCA3治疗的靶点。     

Clusterin in neurological disorders: molecular perspectives and clinical relevance

Firstly discovered in rete testis fluid, clusterin is a glycoprotein present in most of the other biological fluids. Several isoforms of clusterin are encoded from a single gene located on chromosome 8 in human species. Among the different isoforms, the secreted form of clusterin is expressed by a variety of tissues, including the nervous system under normal conditions. This form is presumed to play an anti-apoptotic role and seems to be a major determinant in cell survival and neuroplasticity after stroke. In animal models of this pathology, both neuronal and astroglial subpopulations express high levels of clusterin early after the ischemic damage. Recent lines of evidence point also to its possible involvement in neurodegenerative disorders. It is thought that in Alzheimer's disease the association between amyloidogenic peptides and clusterin contributes to limit Aβ species misfolding and facilitates their clearance from the extracellular space. Thus, intercellular and intracellular factors that modulate local clusterin expression in the nervous system may represent potent targets for neurodegenerative disease therapies. In this review we provide a critical overview of the most recent data on the involvement of clusterin in neurodegenerative diseases with special reference to their putative clinical relevance.     

伴有皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病：附一个家系临床

目的 探讨伴有皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病（ｃｅｒｅｂｒａｌ ａｕｔｏｓｏｍｅ ｄｏｍｉｎａｎｔ ａｒｔｅｒｉｏｐａｔｈｙ ｗｉｔｈ ｓｕｂｃｏｒｔｉｃａｌ ｉｎｆａｒｃｔｓ ａｎｄ ｌｅｕｋｏｅｎｃｅｐｈａｌｏｐａｔｈｙ,ＣＡＤＡＳＩＬ）患者的临床特点和诊断方法。方法 对１例ＣＡＤＡＳＩＬ患者及其亲属的临床表现、影像学（ＭＲＩ、ＣＴ）特点及基因改变等方面进行了系统研究,并针对性地进行了肌肉及神经活检。结果 患者的临床表现为记忆力减退,有脑卒中发作;ＭＲＩ、ＣＴ检查可见多发性梗死、脑白质变性、脑组织活检示小血管玻璃样变、嗜锇颗粒;ＮＯＴＣＨ３第４外显子错义突变以及明确的家族史,没有高血压、动脉硬化,故符合ＣＡＤＡＳＩＬ的诊断标准。结论 本病通过临床特点、影像学改变、基因检测及皮肤活检,可在生     

眼咽型远端型肌病二家系的临床、病理及分子学特点

目的 探讨2个眼咽型远端型肌病(OPDM)家系的临床、病理及分子生物学特点.方法 对2个家系的先证者行血清肌酶、肌电图、肌肉活体组织检查、肌肉酶组织染色及电镜分析,并于复诊时提取其静脉血DNA样本,进一步行编码多聚腺苷酸结合蛋白核1(PABPN1)、GNE基因突变分析.结果 家系1为同代3兄弟发病,家系2为2代4人发病.起病以发音困难伴双下肢无力居多；以发音及吞咽困难为表现的咽部肌群受累较突出.肌肉超微结构电镜分析未见到眼咽型肌营养不良样核内包涵体,2家系先证者PABPN1基因GCN重复拷贝数均为正常(10次,GCG6GCA3GCG1),且GNE基因2～12号外显子均未发现突变.结论 2个OPDM家系起病年龄、形式与日本患者类似,但肌肉受累方式有所不同.家系1为中国首个常染色体隐性遗传OPDM家系.本研究结果证实OPDM是一个表型、病理、遗传学独立的肌病实体.     

Sequence motifs of myelin membrane proteins: Towards the molecular basis of diseases

The shortest sequence of amino acids in protein containing functional and structural information is a “motif.” To understand myelin protein functions, we intensively searched for motifs that can be found in myelin proteins. Some myelin proteins had several different motifs or repetition of the same motif. The most abundant motif found among myelin proteins was a myristoylation motif. Bovine MAG held 11 myristoylation motifs and human myelin basic protein held as many as eight such motifs. PMP22 had the fewest myristoylation motifs, which was only one; rat PMP22 contained no such motifs. Cholesterol recognition/interaction amino‐acid consensus (CRAC) motif was not found in myelin basic protein. P2 protein of different species contained only one CRAC motif, except for P2 of horse, which had no such motifs. MAG, MOG, and P0 were very rich in CRAC, three to eight motifs per protein. The analysis of motifs in myelin proteins is expected to provide structural insight and refinement of predicted 3D models for which structures are as yet unknown. Analysis of motifs in mutant proteins associated with neurological diseases uncovered that some motifs disappeared in P0 with mutation found in neurological diseases. There are 2,500 motifs deposited in a databank, but 21 were found in myelin proteins, which is only 1% of the total known motifs. There was great variability in the number of motifs among proteins from different species. The appearance or disappearance of protein motifs after gaining point mutation in the protein related to neurological diseases was very interesting. © 2013 Wiley Periodicals, Inc.     

Low molecular weight thiol amides attenuate MAPK activity and protect primary neurons from Abeta(1-42) toxicity

Oxidative stress caused by various stimuli lead to oxidation of glutathione (GSH), the major redox power of the cell. Amyloid beta [Abeta(1-42)] is one of the key components of senile plaques and is involved in the progress initiation and triggers of Alzheimer's disease (AD). Lower GSH levels correlated with the activation of mitogen-activated proteins kinases (MAPK) have been demonstrated in AD, Parkinson's disease (PD) and other neurodegenerative disorders and have been proposed to play a central role in the deterioration of the aging and neurodegenerative brain. In this study, we evaluated the ability of low molecular weight thiol amides, N-acetyl cysteine amide (AD4) that replenishes GSH levels, N-acetyl glycine cysteine amide (AD7) and N-acetyl-Cys-Gly-Pro-Cys-amide (CB4) to protect primary neuronal culture against the oxidative and neurotoxic effects of Abeta(1-42) and to inhibit cisplatin- and hydrogen-peroxide-induced phosphorylation of two MAP kinases (MAPK), p38 and ERK1/2, in NIH3T3 cells. Cell death induced by Abeta(1-42) in primary neuronal cells was reversed by the thiol amides. Likewise, protein oxidation, loss of mitochondrial function and DNA fragmentation all returned to control levels by pretreatment with the three thiol amides. Elevated phosphorylation of ERK1/2 and p38 induced by cisplatin or H2O2 in NIH3T3 cells was lowered by AD4, AD7 and CB4 in a dose-dependent manner. Taken together, these results suggest that the thiol amides AD4, AD7 and CB4 protect neuronal cells against Abeta(1-42) toxicity by attenuating oxidative stress in correlation with inhibiting the MAPK phosphorylation cascade. These results are consistent with the notion that these small molecular thiol amides may play a viable protective role in the oxidative and neurotoxicity induced by Abeta(1-42) in AD brain.     

Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus

Purpose: Polymerase gamma (POLG) is the sole enzyme in the replication of mitochondrial DNA (mtDNA). Numerous mutations in the POLG1 gene have been detected recently in patients with various phenotypes including a classic infantile-onset Alpers-Huttenlocher syndrome (AHS). Here we studied the molecular etiology of juvenile-onset AHS manifesting with status epilepticus and liver disease in three teenagers.
Patients and Methods: We examined 14- and 17-year-old female siblings (patients 1 and 2) and an unrelated 15-year-old girl (patient 3) with juvenile-onset AHS, sequenced POLG1, and the entire mtDNA, examined mtDNA deletions by amplification of the full-length mtDNA with the long PCR method and used real-time PCR to quantify mtDNA in the tissue samples.
Results: The initial manifestations were migraine-like headache and epilepsy, and the terminal manifestations status epilepticus and hepatic failure. A homozygous W748S mutation in POLG1 was detected in the three patients. No deletions or pathogenic point mutations were found in mtDNA, but all three patients had mtDNA depletion.
Conclusions: POLG mutations should be considered in cases of teenagers and young adults with a sudden onset of intractable seizures or status epilepticus, and acute liver failure. The W748S POLG1 mutation seems to lead to tissue-specific, partial mtDNA depletion in patients with juvenile-onset Alpers syndrome. Valproic acid should be avoided in the treatment of epileptic seizures in these patients.     

干燥综合征患者伴神经系统损害7例临床及病理变化

目的 探讨干燥综合征患者伴神经系统损害患者的临床及其肌肉和周围神经病理改变。方法 对7例患者的临床表现、实验室检查进行系统描述,对肌肉及神经组织进行组织学及组织化学染色,并行电子显微镜检查。结果 2例神经组织活检可见有髓神经纤维严重脱失,有髓神经纤维数目严重减少,轻度轴索变性。5例肌肉活检可见肌纤维萎缩、坏死,血管周围有单核样细胞浸润,肌内衣有微血管炎的病理改变。结论 干燥综合征患者的肌肉或周围神经并发症在疾病的早期即可出现,肌肉或神经活检可证实有无损害及其严重程度,早期诊断及早期治疗对改善干燥综合征患者伴神经系统损害者的预后是很有 必要的。