目的：探讨精神分裂症断裂基因（DISC1）rs821633,rs1000731单核苷酸多态性（SNP）与阿尔茨海默病（AD）的关系.方法提取中国上海汉族441例 AD 患者和749名健康对照组的 DNA,采用 Taqman 探针 SNP 基因分型技术测定 DISC1基因 SNP rs821...目的：探讨精神分裂症断裂基因（DISC1）rs821633,rs1000731单核苷酸多态性（SNP）与阿尔茨海默病（AD）的关系.方法提取中国上海汉族441例 AD 患者和749名健康对照组的 DNA,采用 Taqman 探针 SNP 基因分型技术测定 DISC1基因 SNP rs821633和 rs1000731位点的等位基因及基因型,检测两组受试者等位基因及基因型的频率分布差异.结果两组受试者中 rs821633不符合Hardy－Weinberg 平衡定律给予舍弃,rs1000731符合 Hardy－ Weinberg 平衡定律纳入,rs1000731位点的等位基因及基因型在两组受试者中分布比较,差异无统计学意义（P ＞0．05）.结论 DISC1基因SNP rs1000731与 AD 无明显关联.展开更多
精神分裂症断裂基因1(disrupted in schizophrenia 1,DISC1)是多种精神疾病中的一个关键的遗传学危险因素。DISC1能够与磷酸二酯酶4(phosphodiesterase 4,PDE4)相互作用形成复合物,这可能是一些精神疾病的关键分子机制。PDE4能够水解cAM...精神分裂症断裂基因1(disrupted in schizophrenia 1,DISC1)是多种精神疾病中的一个关键的遗传学危险因素。DISC1能够与磷酸二酯酶4(phosphodiesterase 4,PDE4)相互作用形成复合物,这可能是一些精神疾病的关键分子机制。PDE4能够水解cAMP,DISC1可通过调节PDE4的活性进而发挥调节cAMP在细胞内的信号转导功能。已有研究证实,在一些精神疾病患者中,DISC1和PDE4基因表达均发生了变化。DISC1突变导致其表达产物与PDE4的相互作用减弱,结果之一是降低脑PDE4的活性。DISC1与PDE4之间的相互作用的改变可能是精神分裂症及抑郁症等疾病症状产生的基础。展开更多
A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk.In humans,a large proportion of mental disorders are accompanied by impairments in risk avoidance.One of th...A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk.In humans,a large proportion of mental disorders are accompanied by impairments in risk avoidance.One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1(DISC1),and animal models in which this gene has some level of dysfunction show emotion-related impairments.However,it is not known whether DISC1 mouse models have an impairment in avoiding potential risks.In the present study,we used DISC1-N terminal truncation(DISC1-N^(TM))mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze(EPM)and showed reduced social preference in a three-chamber social interaction test.Following EPM tests,c-Fos expression levels indicated that the nucleus accumbens(NAc)was associated with risk-avoidance behavior in DISC1-N^(TM)mice.In addition,in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons(FS)in the NAc were significantly lower in DISC1-N^(TM)mice than in wild-type(WT)mice.In addition,in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin(PV)neurons in the NAc of DISC1-N^(TM)mice than in WT controls.The impairment of risk avoidance in DISC1-N^(TM)mice was rescued using optogenetic tools that activated NAcPV neurons.Finally,inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N^(TM)mice during tests on the elevated zero maze.Taken together,our findings confirm an impairment in risk avoidance in DISC1-N^(TM)mice and suggest that reduced excitability of NAc^(PV) neurons is responsible.展开更多
Disrupted-In-Schizophrenia 1(DISC1),a susceptibility gene for major psychiatric disorders,encodes a multifunctional protein implicated in various aspects of neuronal development.However,the precise role of DISC1 in ne...Disrupted-In-Schizophrenia 1(DISC1),a susceptibility gene for major psychiatric disorders,encodes a multifunctional protein implicated in various aspects of neuronal development.However,the precise role of DISC1 in neuronal polarization has remained elusive.Here,we show that dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons.Expression of phosphodead human DISC1(hDISC1 AA)delays the morphological transition from multipolar to uni/bipolar stages in mouse cortical neuronal cultures.hDISC1 AAknockin mice exhibit misoriented axon initial segments of cortical projecting neurons,reduced corpus callosum thickness,and schizophrenia-like behavior.Moreover,GSK3β activity is increased in the cortices of these knockin mice,and embryonic administration of GSK3βinhibitor effectively rescues aberrant axon initial segment and corpus callosum,as well as their behavioral deficits.Our findings support a molecular model wherein dephosphorylation of DISC1 at both Ser58 and Ser713 leads to enhanced GSK3βactivity and subsequent inhibition of axon formation,potentially representing a key pathogenic mechanism underlying psychiatric disorders related to DISC1 dysfunction.展开更多
Psychiatric disorders arc highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points toward D1SCI being one of the genes that i...Psychiatric disorders arc highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points toward D1SCI being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain.展开更多
Objective: The aim of the present study was to check the potential interaction of two neurodevelopmental proteins, Disc1 and Gas7, in the adult mice brain. Methods: Twenty-four male Swiss albino mice were used for the...Objective: The aim of the present study was to check the potential interaction of two neurodevelopmental proteins, Disc1 and Gas7, in the adult mice brain. Methods: Twenty-four male Swiss albino mice were used for the study. The mice were 12 weeks old in the beginning of the experiment. Immunohistochemistry and co-immunofluorescence were performed on the coronal sections of mice brain and immunoblotting and co-immunoprecipitation were done on the whole brain lysate. Results: Data from immunohistochemistry and co-immunofluorescence indicate the occurrence and co-localization of Disc1 and Gas7 proteins in soma and projections of the brain cells. Immunostaining was observed in cerebral cortex, hypothalamus, midbrain, pons, medulla oblongata and CA3 of hippocampus of the brain. The data from Immunoblotting and co-immunoprecipitation validates the presence and interaction of Disc1 and Gas7 protein in whole brain lysate. Conclusion: Data indicates the potential interaction of Disc1 and Gas7 protein in adult brain. The study highlights the need for further research on Disc1-Gas7 protein interaction in brain development and neuro-disorders.展开更多
基金support from the National Key Basic Research and Devdopment Program(973),Grant No.2011CB707805the Natural Science Foundation of China,Grant Nos.81000582 and 60831004+1 种基金the National High Technology Research and Development Program of China(863 Program), Grant No.2009AA02Z302The Beijing Nova Program,Grant No.2010B061
基金supported by the National Natural Science Foundation of China(8117127281301159)+5 种基金the Shanghai Training Plan for Excellent Academic Leaders in Public Health(GWDTR201227)the National Key Clinical Disciplines of the Office of Medical Affairs of the Chinese Ministry of Health at the Shanghai Mental Health Center(OMA-MH2011-873)the Training Plan for Excellent Academic Leaders of the Shanghai Health System(XBR2013087)the Shanghai Mental Health Center Research Grant(2014-YJ-042015-YJGJ-03)
文摘精神分裂症断裂基因1(disrupted in schizophrenia 1,DISC1)是多种精神疾病中的一个关键的遗传学危险因素。DISC1能够与磷酸二酯酶4(phosphodiesterase 4,PDE4)相互作用形成复合物,这可能是一些精神疾病的关键分子机制。PDE4能够水解cAMP,DISC1可通过调节PDE4的活性进而发挥调节cAMP在细胞内的信号转导功能。已有研究证实,在一些精神疾病患者中,DISC1和PDE4基因表达均发生了变化。DISC1突变导致其表达产物与PDE4的相互作用减弱,结果之一是降低脑PDE4的活性。DISC1与PDE4之间的相互作用的改变可能是精神分裂症及抑郁症等疾病症状产生的基础。
基金This work was supported by the National Natural Science Foundation of China(31671116,31761163005,31800881,and 91132306)the International Big Science Program Cultivation Project of Chinese Academy of Sciences(172644KYS820170004)+3 种基金the External Cooperation Program of the Chinese Academy of Sciences(172644KYSB20160057)Science and Technology Program of Guangzhou Municipality(202007030001)the Key-Area Research and Development Program of Guangdong Province(2018B030331001 and 2018B03033600)Shenzhen Government Basic Research Grants(JCYJ20200109115405930 and JCYJ20200109150717745).
文摘A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk.In humans,a large proportion of mental disorders are accompanied by impairments in risk avoidance.One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1(DISC1),and animal models in which this gene has some level of dysfunction show emotion-related impairments.However,it is not known whether DISC1 mouse models have an impairment in avoiding potential risks.In the present study,we used DISC1-N terminal truncation(DISC1-N^(TM))mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze(EPM)and showed reduced social preference in a three-chamber social interaction test.Following EPM tests,c-Fos expression levels indicated that the nucleus accumbens(NAc)was associated with risk-avoidance behavior in DISC1-N^(TM)mice.In addition,in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons(FS)in the NAc were significantly lower in DISC1-N^(TM)mice than in wild-type(WT)mice.In addition,in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin(PV)neurons in the NAc of DISC1-N^(TM)mice than in WT controls.The impairment of risk avoidance in DISC1-N^(TM)mice was rescued using optogenetic tools that activated NAcPV neurons.Finally,inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-N^(TM)mice during tests on the elevated zero maze.Taken together,our findings confirm an impairment in risk avoidance in DISC1-N^(TM)mice and suggest that reduced excitability of NAc^(PV) neurons is responsible.
基金supported by the National Natural Science Foundation of China(92254301,32230048,31971116,31801208)Beijing Municipal Natural Science Foundation(5202005)+2 种基金the State Research and Development Program(2024YFA0916804)R&D Program of Beijing Municipal Education Commission(KM201910025025)Laboratory for Clinical Medicine,Capital Medical University。
文摘Disrupted-In-Schizophrenia 1(DISC1),a susceptibility gene for major psychiatric disorders,encodes a multifunctional protein implicated in various aspects of neuronal development.However,the precise role of DISC1 in neuronal polarization has remained elusive.Here,we show that dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons.Expression of phosphodead human DISC1(hDISC1 AA)delays the morphological transition from multipolar to uni/bipolar stages in mouse cortical neuronal cultures.hDISC1 AAknockin mice exhibit misoriented axon initial segments of cortical projecting neurons,reduced corpus callosum thickness,and schizophrenia-like behavior.Moreover,GSK3β activity is increased in the cortices of these knockin mice,and embryonic administration of GSK3βinhibitor effectively rescues aberrant axon initial segment and corpus callosum,as well as their behavioral deficits.Our findings support a molecular model wherein dephosphorylation of DISC1 at both Ser58 and Ser713 leads to enhanced GSK3βactivity and subsequent inhibition of axon formation,potentially representing a key pathogenic mechanism underlying psychiatric disorders related to DISC1 dysfunction.
文摘Psychiatric disorders arc highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points toward D1SCI being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain.
文摘Objective: The aim of the present study was to check the potential interaction of two neurodevelopmental proteins, Disc1 and Gas7, in the adult mice brain. Methods: Twenty-four male Swiss albino mice were used for the study. The mice were 12 weeks old in the beginning of the experiment. Immunohistochemistry and co-immunofluorescence were performed on the coronal sections of mice brain and immunoblotting and co-immunoprecipitation were done on the whole brain lysate. Results: Data from immunohistochemistry and co-immunofluorescence indicate the occurrence and co-localization of Disc1 and Gas7 proteins in soma and projections of the brain cells. Immunostaining was observed in cerebral cortex, hypothalamus, midbrain, pons, medulla oblongata and CA3 of hippocampus of the brain. The data from Immunoblotting and co-immunoprecipitation validates the presence and interaction of Disc1 and Gas7 protein in whole brain lysate. Conclusion: Data indicates the potential interaction of Disc1 and Gas7 protein in adult brain. The study highlights the need for further research on Disc1-Gas7 protein interaction in brain development and neuro-disorders.
