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Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile x syndrome

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Protein & Cell 2022年第3期13卷 203-219页

作者： Chaojuan Yang Yonglu Tian Feng Su Yangzhen Wang Mengna Liu Hongyi Wang Yaxuan Cui Peijiang Yuan xiangning Li Anan Li Hui Gong Qingming Luo Desheng Zhu Peng Cao Yunbo Liu xunli Wang Min-hua Luo Fuqiang xu Wei xiong Liecheng Wang xiang-yao Li Chen Zhang State Key Laboratory of Membrane Biology PKU-IDG/McGovern Institute for Brain ResearchSchool of Life SciencesPeking UniversityBeijing 100871China School of Basic Medical Sciences Beijing Key Laboratory of Neural Regeneration and RepairCapital Medical UniversityBeijing 100069China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China School of Mechanical Engineering and Automation Beihang UniversityBeijing 100191China School of Life Sciences Tsinghua UniversityBeijing 100084China Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and TechnologyWuhan 430074China State Key Laboratory of Brain and Cognitive Sciences Institute of BiophysicsChinese Academy of Sciences(CAS)Beijing 100101China Institute of Laboratory Animal Science Peking Union Medical College/Chinese Academy of Medical ScienceBeijing 100021China Laboratory Animal Center Fujian University of Tradition Chinese MedicineFuzhou 350122China State Key Laboratory of Virology CAS Center for Excellence in Brain Science andIntelligence TechnologyWuhan Institute of VirologyCASWuhan 430071China Center for Brain Science Key Laboratory of Magnetic Resonance in Biological Systems and State Key Laboratory of Magnetic Resonance and Atomic and Molecular PhysicsWuhan Institute of Physics and MathematicsCASCenter for Excellence in Brain Science and Intelligence TechnologyChinese Academy of SciencesWuhan 430071China Department of Physiology Anhui Medical UniversityHefei 230032China Department of Physiology Institute of Neuroscience and Collaborative Innovation Center for Brain ScienceSchool of MedicineZhejiang UniversityHangzhou 310058China

Many people affected by fragile x syndrome(FxS)and autism spectrum disorders have sensory processing deficits,such as hypersensitivity to auditory,tactile,and visual stimuli.Like FxS in humans,loss of Fmr1 in rodents also cause sensory,behavioral,and cognitive deficits.However,the neural mechanisms underlying sensory impairment,especially vision impairment,remain unclear.It remains elusive whether the visual processing deficits originate from corrupted inputs,impaired perception in the primary sensory cortex,or altered integration in the higher cortex,and there is no effective treatment.In this study,we used a genetic knockout mouse model(Fmr1^(KO)),in vivo imaging,and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex(V1).Specifically,Fmr1^(KO) mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli.This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons.These effects were ameliorated by the acute application of GABAA receptor activators,which enhanced the activity of inhibitory neurons,or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice.Overall,V1 plays an important role in the visual abnormalities of Fmr1^(KO) mice and it could be possible to rescue the sensory disturbances in developed FxS and autism patients.

关键词： autism spectrum disorder calcium imaging fragile x syndrome primary visual cortex visual hypersensitivity

Population-based carrier screening and prenatal diagnosis of fragile x syndrome in East Asian populations

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Journal of Genetics and Genomics 2021年第12期48卷 1104-1110页

作者： Qiwei Guo Yih-Yuan Chang Chien-Hao Huang Yu-Shan Hsiao Yu-Chiao Hsiao I-Fan Chiu Yulin Zhou Haixia Zhang Tsang-Ming Ko United Diagnostic and Research Center for Clinical Genetics Women and Children's HospitalSchool of Medicine&School of Public HealthXiamen UniversityXiamenFujian 361102China Genephile Bioscience Laboratory Ko's Obstetrics and GynecologyTaipei 100TaiwanChina Biofast Biotechnology Co. Ltd.XiamenFujian 361102China

Identification of carriers of fragile x syndrome(FxS) with the subsequent prenatal diagnosis and knowledge of FxS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FxS carriers.The prevalence of FxS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization;the integral risks of full mutation expansion were approximately 6.0%,43.8%, and 100% for premutation alleles with 55—74, 75—89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG(adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75—89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FxS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FxS in East Asian populations to date. The FxSassociated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FxS intervention.

关键词： AGG interruption East Asian population fragile x syndrome Population-based carrier screening Prenatal diagnosis Cost-effectiveness analysis

Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of fragile x syndrome

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Neuroscience Bulletin 2021年第7期37卷 973-984页

作者： Juan Zhao Jin xue Tengfei Zhu Hua He Huaixing Kang xuan Jiang Wen Huang Ranhui Duan Center for Medical Genetics School of Life SciencesCentral South UniversityChangsha 410078China Hunan Key Laboratory of Medical Genetics Central South UniversityChangsha 410078China Hunan Key Laboratory of Animal Models for Human Diseases Central South UniversityChangsha 410078China

fragile x syndrome(FxS)is the leading inherited cause of intellectual disability,resulting from the lack of functional fragile x mental retardation protein(FMRP),an mRNA binding protein mainly serving as a translational regulator.Loss of FMRP leads to dysregulation of target mRNAs.The Drosophila model of FxS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network.Yet the FMRP targets involved in circadian regulation have not been identified.Here,we identified collapsing response mediator protein(CRMP)mRNA as a target of FMRP.Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons(ventral lateral neurons)in dfmr1 mutant flies.Furthermore,specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors.Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation.Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FxS Drosophila.

关键词： fragile x syndrome FMRP CRMP Circadian rhythm

Integrated transcriptome analysis of human iPS cells derived from a fragile x syndrome patient during neuronal differentiation

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Science China(Life Sciences) 2016年第11期59卷 1093-1105页

作者： Ping Lu xiaolong Chen Yun Feng Qiao Zeng Cizhong Jiang xianmin Zhu Guoping Fan Zhigang xue Tongji Stem Cell Research Center Tongji University School of MedicineShanghai 200092China Tongji University School of Life Sciences and TechnologyShanghai 200092China Department of Human Genetics David Geffen School of MedicineUniversity of California Los AngelesLos Angeles CA 90095USA Translational Center for Stem Cell Research Tongji HospitalDepartment of Regenera-tive MedicineTongji University School of MedicineShanghai 200065China Tongji University Suzhou Institute Suzhou 215101China

fragile x syndrome(FxS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile x mental retardation 1(FMR1), leading to decreased or absent expression of its encoded fragile x mental retardation protein(FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here,we performed in-vitro neuronal differentiation of human induced pluripotent stem(iPS) cells that were derived from fibroblasts of a FxS patient(FxS-iPSC). We then performed RNA-seq and examined the transcriptional misregulation at each intermediate stage during in-vitro differentiation of FxS-iPSC into neurons. After thoroughly analyzing the transcriptomic data and integrating them with those from other platforms, we found up-regulation of many genes encoding TFs for neuronal differentiation(WNT1, BMP4,POU3F4, TFAP2 C, and PAx3), down-regulation of potassium channels(KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9,and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FxS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FxS patients. In conclusion, we demonstrated that the FMRP deficiency in FxS patients has significant impact on the gene expression patterns during development, which will help to discover potential targeting candidates for the cure of FxS symptoms.

关键词： fragile x syndrome induced pluripotent stem cells neuronal differentiation transcriptome

Molecular medicine of fragile x syndrome: based on known molecular mechanisms

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世界儿科杂志:英文版 2016年第1期12卷 19-27页

作者： Shi-Yu Luo Ling-Qian Wu Ran-Hui Duan State Key Laboratory of Medical Genetics&School of Life Sciences Central South UniversityChangshaChina

Background:Extensive research on fragile x mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile x syndrome(FxS).In light of these findings,several clinical trials are now underway for therapeutic translation to humans.Data sources:Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov.The search terms included"fragile x syndrome","FxS and medication","FxS and therapeutics"and"FxS and treatment".Based on the publications identified in this search,we reviewed the neuroanatomical abnormalities in FxS patients and the potential pathogenic mechanisms to monitor the progress of FxS research,from basic studies to clinical trials.Results:The pathological mechanisms of FxS were categorized on the basis of neuroanatomy,synaptic structure,synaptic transmission and fragile x mental retardation protein(FMRP)loss of function.The neuroanatomical abnormalities in FxS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FxS behavioural manifestations.Mechanism-directed molecular medicines were classified according to their target pathological mechanisms,and the most recent progress in clinical trials was discussed.Conclusions:Current mechanism-based studies and clinical trials have greatly contributed to the development of FxS pharmacological therapeutics.Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FxS patients may help to improve the effi cacy of treatments.

关键词： clinical trial fragile x syndrome mechanism-based treatment

Lithium chloride ameliorates learning and memory ability and inhibits glycogen synthase kinase-3 beta activity in a mouse model of fragile x syndrome

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Neural Regeneration Research 2011年第31期6卷 2452-2459页

作者： Shengqiang Chen xuegang Luo Quan Yang Weiwen Sun Kaiyi Cao xi Chen Yueling Huang Lijun Dai Yonghong Yi Department of Human Anatomy and Neurobiology College of Basic Medicine Central South University Changsha 410013 Hunan Province China Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province the Ministry of Education Institute of Neuroscience Second Affiliated Hospital of Guangzhou Medical College Guangzhou 510260 Guangdong Province China Laboratory Animal Research Center of Guangzhou Medical College Guangzhou 510182 Guangdong Province China

In the present study,Fmr1 knockout mice （KO mice） were used as the model for fragile x syndrome.The results of step-through and step-down tests demonstrated that Fmr1 KO mice had shorter latencies and more error counts,indicating a learning and memory disorder.After treatment with 30,60,90,120,or 200 mg/kg lithium chloride,the learning and memory abilities of the Fmr1 KO mice were significantly ameliorated,in particular,the 200 mg/kg lithium chloride treatment had the most significant effect.Western blot analysis showed that lithium chloride significantly enhanced the expression of phosphorylated glycogen synthase kinase 3 beta,an inactive form of glycogen synthase kinase 3 beta,in the cerebral cortex and hippocampus of the Fmr1 KO mice.These results indicated that lithium chloride improved learning and memory in the Fmr1 KO mice,possibly by inhibiting glycogen synthase kinase 3 beta activity.

关键词： fragile x syndrome Fmr1 knockout mice step-down test step-through test learning and memory glycogen synthase kinase 3 beta lithium chloride

A Rapid Screening and Diagnosis on fragile x syndrome by PCR

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Journal of Huazhong University of Science and Technology(Medical Sciences) 1999年第2期19卷 66-69页

作者：陈敬春杨爱德费洪宝金润铭何美娟王碧玉

Polymerase chain reaction (PCR) technique combined with direct detection by silver staining on denaturing DNA sequencing gel was used to analyze the (CGG)n repeats within the FMR1 gene on 169 suspected patients with mental retardation and 33 kindreds of 6 fragile x families. The results showed that : (1) No PCR products were detected in 3 males in the suspected group. (2) In the fragile x family studies, the 5 male probands failed to show any PCR products. (3) Diplex PCR with the primers flanking the FRAxE locus was used to serve as an internal control for the 8 above mentioned males and only normal products of the FRAxE locus were detected, indicating that the possibility of false negative results of the FRAxA locus could be eliminated. These findings suggested that analysis of (CGG)n repeat within the FMR1 gene by PCR technique could efficiently detect premutation carriers and that negative PCR products in mentally retarded males might highly imply the diagnosis of fragile x syndrome after the false negative results have been excluded by diplex PCR. This PCR assay is suitable for the screening and diagnosis of fragile x syndrome in a large number of populations due to its rapidity, simplicity, stability and reliability.

关键词： fragile x syndrome PCR screening diagnosis

Computation-Based Development of Therapeutic Strategy for fragile x syndrome

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神经药理学报 2019年第Z1期 59-60页

作者： DING Qi Ferzin Sethna WU xue-ting MIAO Zhuang CHEN Ping ZHANG Yue-qi xIAO Hua FENG Wei FENG Yue LI xuan 王红兵 Department of Physiology 2Genetics ProgramMichigan State University Key Laboratory of Synthetic Biology Institute of Plant Physiology and EcologyShanghai Institutes for Biological SciencesChinese Academy of Sciences Department of Pharmacology and Chemical Biology Emory University School of Medicine 密西根州立大学生理系

fragile x syndrome(FxS),caused by mutations in fragile x mental retardation 1 gene(FMR1),is a prevailing genetic disorder of intellectual disability and autism. Currently,there is no efficacious medication for FxS. Here,we use transcriptome landscape as a holistic molecular phenotype/endpoint to identify potential therapeutic intervention. Through in silico screening with public gene signature database,computational analysis of transcriptome profile in Fmr1 knockout(KO) neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Through experimental validation,we find that systemic administration of trifluoperazine attenuates multiple FxS-and autism-related behavioral symptoms. Moreover,computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3 K(Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently,trifluoperazine suppresses PI3 K activity and its down-stream targets Akt(protein kinase B) and S6 K1(S6 kinase 1) in neurons. In conclusion,our data demonstrate promising value of gene signature-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders,and suggest trifluoperazine as a potential practical treatment for FxS.

关键词： fragile x syndrome transcriptome signature connectivity MAP mouse model therapeutic development

Reducing histone acetylation rescues cognitive deficits in mouse model of fragile x syndrome

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中国药理学与毒理学杂志 2019年第9期33卷 666-666页

作者： LI Yue Michael ESTOCKTON Brian EEISINGER ZHAO Ying-hua Jessica LMILLER Ismat BHUIYAN GAO Yu WU Zhi-ping PENG Jun-min ZHAO xin-yu Institute of Traditional Chinese Medicine Tianjin University of Traditional Chinese MedicineTianjin 301617China Waisman Center University of Wisconsin-MadisonMadisonWI 53705USA Department of Neuroscience University of Wisconsin-MadisonMadisonWI 53705USA Departments of Structural Biology and Developmental Neurobiology St.Jude Proteomics FacilitySt.Jude Children′s Research Hospital262 Danny Thomas PlaceMemphisTN 38105USA

fragile x syndrome(FxS)is the most prevalent inherited intellectual disability,resulting from a loss of fragile x mental retardation protein(FMRP).Patients with FxS suffer lifelong cognitive disabilities,but the function of FMRP in the adult brain and the mechanism underlying age-related cognitive decline in FxS is not fully understood.Here,we report that a loss of FMRP results in increased protein synthesis of histone acetyltransferase EP300 and ubiquitinationmediated degradation of histone deacetylase HDAC1 in adult hippocampal neural stem cells(NSCs).Consequently,FMRPdeficient NSCs exhibit elevated histone acetylation and age-related NSC depletion,leading to cognitive impairment in mature adult mice.Reducing histone acetylation rescues both neurogenesis and cognitive deficits in mature adult FMRPdeficient mice.Our work reveals a role for FMRP and histone acetylation in cognition and presents a potential novel ther⁃apeutic strategy for treating adult FxS patients.

关键词： fragile x syndrome histone acetylation neural stem cells