中枢单胺类神经递质在酒精依赖中的分子作用机制

酒精依赖是以失去控制地饮用酒精为特征的慢性、复发性脑疾病, 业已成为严重的社会问题。中枢单胺类神经递质(包括多巴胺、5-羟色胺等)在酒精依赖症的发生、发展和系统功能失调中发挥着重要作用。文章探讨了单胺类神经递质关键调控点多巴胺受体、5-羟色胺受体、转运体、酪氨酸羟化酶、色氨酸羟化酶及单胺氧化酶基因等在酒精依赖中的作用机制, 结合本实验室在基因敲除小鼠模型方面的研究进展提出了酒精依赖分子机制的研究策略。在系统评述中枢单胺类神经递质介导的酒精依赖分子作用机制的基础上, 结合本实验室在酪氨酸羟化酶激活剂钙调蛋白依赖的蛋白激酶Ⅱ方面的研究成果探讨了可用于酒精依赖症治疗的作用靶点, 提出通过调整基因调控区的甲基化程度和改变pre-mRNA的选择性剪切等表观遗传学策略预防和治疗酒精依赖症, 同时根据基因多态性研究结果提出对酒精依赖症患者进行个性化预防和治疗的新策略。     

酒精依赖相关基因的遗传多态性

酒精依赖综合征受到复杂的生理、心理、个体遗传及环境等诸多因素的影响。有关研究已经证实了某些候选基因和酒精依赖密切相关。文章主要对与酒精依赖相关的酒精代谢关键酶(乙醇脱氢酶和乙醛脱氢酶以及细胞色素P450 2E1)基因以及调节神经递质作用的酶和受体(儿茶酚氧位甲基转移酶, 多巴胺受体D2、D4, μ阿片受体)基因遗传多态性研究作一综述。     

帕金森病会表现为母系遗传吗?

<正>答:帕金森病(Parkinson disease,PD)是一种较常见的神经退行性疾病,通常是由于黑质-纹状体多巴胺(Dopamine,DA)能神经元的进行性损害导致的运动功能障碍。目前已经发现多个与家族性PD相关的基因,其中表现为常染色体显性遗传(AD)的基因有:突触核蛋白基因(α-synuclein,SNCA)(PARK1PARK4)、UCHL1基因(PARK5)、LRRK2基因     

《酒精中毒：临床与实验研究》：人体酒精依赖同基因有关

美国弗吉尼亚大学医学部的研究人员发现,血清素的运输蛋白SLC6A4基因在影响酒精依赖者的饮酒强度方面起关键作用。这是科学家首次发现酒精依赖的强度同基因的联系,研究人员希望,在未来能够通过基因靶向疗法缓解嗜酒者依赖酒精的程度,相关论文发表在近期出版的《酒精中毒：临床与实验研究》（Alcoholism—Clinical and Experimental Research）杂志上。     

云南汉族人群5-羟色胺转运体基因启动子区多态性与酒精依赖的相关性

为了探讨云南汉族人群中5-羟色胺转运体基因启动子区多态性(5-HTTLPR)与酒精依赖的关联性, 文章采用PCR扩增和DNA测序技术, 对云南地区118例酒精依赖患者和214例健康对照个体进行了5-HTTLPR的基因多态性分析。结果表明: 酒精依赖患者组和正常对照组的5-HTTLPR的基因型分布存在显著性差异, L/L和L/S基因的携带者人群嗜酒发生率显著低于S/S基因型人群(OR: 0.581, P=0.026)。S和L等位基因频率在两组间无统计学差异(χ²=2.594, P=0.107), 但其分布存在种族差异性。因此, 云南地区人群中5-HTTLPR多态与酒精依赖存在相关性, L/L和L/S基因型可能是降低酒精依赖发病的影响因子之一。     

帕金森病相关基因功能研究进展

帕金森病(Parkinson’s disease,PD)是一种较为常见的锥体外系疾病,主要症状是运动减少、肌强直和震颤;主要病理特征是黑质致密区多巴胺神经元缺失,剩余神经元含有Lewy小体。PD的发病机制尚未完全清楚,一般认为与年龄及环境因素相关。近年来PD遗传学研究取得了长足的进步,确定了遗传因素在PD发病过程中的重要作用,发现并鉴定了多个与帕金森病相关的基因:SNCA、LRRK、PINK1、parkin、DJ1和UCHL1等。文章对上述相关基因的功能研究进展进行综述,为进一步探讨PD发病机制提供参考。     

HTR2A基因多态性与云南彝族酒精依赖关联性研究

目的：探讨酒精依赖和云南彝族5-羟色胺2A受体（HTR2A）基因多态之间的关系。方法：采用PCR-RFLP技术对330健康人（对照组）和110名酒精依赖者（病例组）的5-HT2A受体基因的遗传多态性进行检测。结果：在440例样本中共检测到2种等位基因A和G,三种基因型AA,AG,GG．三种基因型在对照组中频率分别是38．5％,55．8％,5．8％;在病例组中的频率分别是30％,63．6％,6．4％。结论：在云彝族人群中,HTR2A基因rs6311（A－1438G）位点与酒精依赖无显著关联,HTR2A基因rs6311（A-1438G）位点在云南汉族和云南彝族酒精依赖组中无显著差异,但是在健康对照组中存在关联性．     

不同行为表现的蜜蜂脑部多巴胺及其受体基因的检测分析

【目的】对不同行为表现的意大利蜜蜂Apis mellifera ligustica工蜂脑部多巴胺及其受体基因进行检测。【方法】从蜜蜂观察箱中采集不同行为表现的工蜂,解剖其脑部,用高效液相色谱-电化学检测器和实时荧光PCR仪分别检测多巴胺含量和受体基因相对表达量,并进行计算分析研究。【结果】建立了不同行为表现的蜜蜂脑部多巴胺及受体基因的研究方法。意大利蜜蜂哺育蜂脑部的多巴胺含量与新出房工蜂、采集蜂、休息状态下的工蜂存在显著差异。多巴胺受体1基因及多巴胺转运体基因在哺育蜂脑部处于高表达状态,4种不同分工的意大利蜜蜂脑部多巴胺受体2基因、受体3基因相对表达量差异不显著。【结论】多巴胺与蜜蜂不同行为表现密切相关,多巴胺受体1基因与转运体基因可能参与蜜蜂哺育行为。     

新疆维吾尔族人载脂蛋白A5-1131T＞C基因多态性对血脂水平的影响

目的:为了探讨新疆维吾尔族人ApoA5基因-1131T＞C基因变异的频率及对血脂水平的影响.方法:对145例经冠脉造影排除冠心病的维吾尔族患者,采用聚合酶链反应-限制性片段长度多态性分析对ApoA5基因-113IT＞C多态性进行检测,比较不同基因型与个体血脂水平的关系.结果:ApoA5-1131C等位基因的频率是33%.TT、TC和CC三种基因型中,TC型与CC型的血甘油三酯(TG)水平明显高于TT型,而以CC型的TG水平最高(P均＜0.05),C携带者(TC CC)较非C携带者(TT)的TG水平增高36.2%[(2.03 1.33)mmol/Lvs(1.49 1.06)mmol/L,P＜0.05].结论:维族人群的ApoA5-113IT＞C基因变异较常见,-1131C等位基因与血TG水平增高有关.     

血脂异常遗传性疾病的研究现状

血脂异常(Dyslipidemia)是指血浆中胆固醇和(或)甘油三酯水平升高, 可导致严重的心血管疾病, 常以冠心病和脑中风为首发表现, 该类疾病严重危害着人们的健康。一些血脂异常疾病具有遗传性, 主要包括孟德尔遗传和多基因遗传。传统检测血脂异常相关基因的方法主要有DNA测序和连锁分析, 适合于孟德尔遗传性血脂异常疾病。最近几年兴起的新一代测序技术(Next-generation sequencing)不仅适用于孟德尔遗传性血脂异常疾病的研究, 同样适用于复杂性血脂异常疾病。2006年至今, 运用全基因组关联分析(Genome wide association study, GWAS)筛出许多与血脂异常疾病相关的基因, 这些基因和早期孟德尔遗传家系确定的基因多数相同。GWAS频谱分析发现, 复杂性疾病相关的基因变异频率存在差异, 并且几乎所有筛查出的与血脂异常疾病相关的单核苷酸多态性(Single nucleotide polymorphisms, SNPs)变异均位于非编码区, 使得人们逐渐对非编码区基因变异展开了研究。血脂异常致病基因的发现和基因变异致病机制的阐明, 为血脂异常疾病提供新的治疗靶点, 并为新一代药物筛选提供新思路。文章对血脂异常遗传性疾病的研究现状进行了综述。     

Inheritance mechnisam of gene SNCA for alcohol dependence

SNCA gene is located in a quantitative trait locus for alcohol preference. Alpha-synuclein coded by SNCA gene can regulate the function of dopamine in multiple levels, and dopamine is an important neurotransmitter in alcohol preference. Variation has been found in SNCA gene carried by alcohol-dependent patients. Meanwhile, significant increase of SNCA gene expression also occurs in alcohol-dependent patients, which is closely associated with the level of alcohol dependence. Therefore, SNCA gene is believed to contribute to genetic mechanism of alcohol dependence. Here, the relationship between SNCA gene and dopamine, the variation and expression of SNCA gene in alcohol-dependent patients were reviewed.     

Contribution of genetics to the concept of risk status for alcohol dependence

The factors involved in the variability of one's own risk for alcohol dependence is multifactorial and mostly unknown. Nevertheless, genetic factors are clearly involved in the risk for the disorder, the impact of addictive genetic factors being evaluated between 30% and 50%. Aggregation studies underline the difficulties of delimiting the boundaries of the phenotype, as some subgroups of alcohol-dependent patients have genetic factors with an increased weight (severe and young-onset disorder, presence of antisocial behavior...). Furthermore, familial studies also showed that the genetic of "addiction" may be more relevant than studying the genetic of one specific dependence. The use of one substance lately abused being probably more dependent of familial and/or environmental features. The discover of susceptibility genes had a greater impact on defining the phenotype than proposing new treatments. Three examples are given in this review. Firstly, le gene coding for the second dopamine receptor may be more specifically involved in severe and comorbid alcohol-dependence. Secondly, the gene coding for the serotonin transporter may increase the suicidal risk in alcohol-dependent patients. Thirdly, the quality of the withdrawal process is partly explained by the existence of a specific genotype of the dopamine transport gene.     

Phytotherapeutic approach to alcohol dependence: New old way?

Alcohol abuse and dependence represent a worldwide problem from both medical and social points of view. In Italy it is estimated that there are about one million alcohol-dependent subjects. The pharmacological treatment of patients with alcohol dependence plays a key role in order to achieve alcohol abstinence and prevent relapse. At present, the possible utility of the complementary medicines in the treatment of alcohol dependence is controversial. In the last years, pre-clinical and clinical data from traditional medicines suggest that novel pharmacological approaches for treatment of alcoholism and alcohol abuse may stem from natural substances. The present review summarizes the findings of the effects of phytotherapy in alcohol addiction.     

Replication of Genome Wide Association Studies of Alcohol Dependence: Support for Association with Variation in ADH1C

Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.     

Reduced Dopamine Transporter Availability and Neurocognitive Deficits in Male Patients with Alcohol Dependence

Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with ^99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and Tridimensional Personality Questionnaire (TPQ) were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001), as well as diminished performance on the WCST (p < 0.001). Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility.     

Overexpression of dopamine D2 receptors reduces alcohol self-administration

The mechanism(s) underlying predisposition to alcohol abuse are poorly understood but may involve brain dopamine system(s). Here we used an adenoviral vector to deliver the dopamine D2 receptor (DRD2) gene into the nucleus accumbens of rats, previously trained to self-administer alcohol, and to assess if DRD2 levels regulated alcohol preference and intake. We show that increases in DRD2 (52%) were associated with marked reductions in alcohol preference (43%), and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. In addition, this DRD2 overexpression similarly produced significant reductions in ethanol non-preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This is the first evidence that overexpression of DRD2 reduces alcohol intake and suggests that high levels of DRD2 may be protective against alcohol abuse.     

Tyrosine kinase inhibition facilitates autophagic SNCA/α-synuclein clearance

The effects of ABL1/ABL inhibition on clearance of SNCA/α-synuclein were evaluated in animal models of α-synucleinopathies. Parkinson disease (PD) is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of SNCA. The tyrosine kinase ABL1 is activated in several neurodegenerative diseases. An increase in ABL1 activity is detected in human postmortem PD brains. Lentiviral expression of SNCA in the mouse SN activates ABL1 via phosphorylation, while lentiviral Abl expression increases SNCA levels. Administration of the brain-penetrant tyrosine kinase inhibitor Nilotinib decreases Abl activity and facilitates autophagic clearance of SNCA in transgenic and lentiviral gene transfer models. Subcellular fractionation demonstrates accumulation of SNCA and hyperphosphorylated MAPT/Tau (p-MAPT) in autophagic vacuoles in SNCA-expressing brains, while Nilotinib treatment leads to protein deposition into the lysosomes, suggesting enhanced autophagic clearance. These data suggest that Nilotinib may be a therapeutic strategy to degrade SNCA in PD and other α-synucleinopathies.