Developmental and epileptic encephalopathies are severe neurological conditions in clinical practice,among which loss-of-function mutations in brain-enriched serine-threonine kinase cyclin dependent kinase like-5(CDKL...Developmental and epileptic encephalopathies are severe neurological conditions in clinical practice,among which loss-of-function mutations in brain-enriched serine-threonine kinase cyclin dependent kinase like-5(CDKL5)exists as one of the most common types.It is unknown,therefore,how precisely CDKL5 mutations lead to neuronal hyper-excitation.A recent study that looked at the connection between voltage-gated calcium channel Cav2.3 and CDKL5 in an experimental context was published in Nature Communications.This study has revealed that Cav2.3,a physi-ological phosphorylation target of CDKL5,would show delayed inactivation and increased cholinergic stimulation in CDKL5 knock out conditions.This would in turn cause neuronal hyperexcitability and related enhanced seizure susceptibility.This work,in our opinion,provided fresh insight into the epileptic encephalopathies linked to CDKL5 and highlighted Cav2.3 as a possible target for it.展开更多
BACKGROUND： The discovery that mutations in cyclin-dependent kinase-like 5 （CDKLS） gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular a...BACKGROUND： The discovery that mutations in cyclin-dependent kinase-like 5 （CDKLS） gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular and genetic basis of CDKL5 disorder. Given the large number of literature published thus far, this review aims to summarize current genetic studies, draw a consensus on proposed molecular functions, and point to gaps of knowledge in CDKL5 research. METHODS： A systematic review process was conducted using the PubMed search engine focusing on CDKL5 studies in the recent ten years. We analyzed these publications and summarized the findings into four sections： genetic studies, CDKL5 expression patterns, molecular functions, and animal models. We also discussed challenges and future directions in each section. RESULTS： On the clinical side, CDKL5 disorder is characterized by early onset epileptic seizures, intellectual disability, and stereotypical behaviors. On the research side, a series of molecular and genetic studies in human patients, cell cultures and animal models have established the causality of CDKL5 to the infantile epileptic encephalopathy, and pointed to a key role for CDKL5 in regulating neuronal function in the brain. Mouse models of CDKL5 disorder have also been developed, and notably, manifest behavioral phenotypes, mimicking numerous clinical symptoms of CDKL5 disorder and advancing CDKL5 research to the preclinical stage. CONCLUSIONS： Given what we have learned thus far, future identification of robust, quantitative, and sensitive outcome measures would be the key in animal model studies, particularly in heterozygous females. In the meantime, molecular and cellular studies of CDKL5 should focus on mechanism-based investigation and aim to uncover druggable targets that offer the potential to rescue or ameliorate CDKL5 disorder-related phenotypes.展开更多
目的研究丝/苏氨酸激酶周期素依赖性激酶样-5(CDKL5)在胃癌组织中的表达,并分析其与胃癌患者的临床病理特征之间的关系。方法应用荧光实时定量PCR法和免疫印迹法分别检测45例胃癌及其癌旁组织中CDKL5 m RNA及蛋白的表达,然后用免疫荧光...目的研究丝/苏氨酸激酶周期素依赖性激酶样-5(CDKL5)在胃癌组织中的表达,并分析其与胃癌患者的临床病理特征之间的关系。方法应用荧光实时定量PCR法和免疫印迹法分别检测45例胃癌及其癌旁组织中CDKL5 m RNA及蛋白的表达,然后用免疫荧光方法检测CDKL5蛋白在AGS和MKN-45胃癌细胞株中的表达情况。结果 CDKL5 m RNA和蛋白在胃癌组织中的表达均明显高于其在相应的癌旁组织中的表达(P<0.05);CDKL5 m RNA的表达与胃癌患者的年龄(P=0.033)、血管浸润(P=0.007)、T分期(P=0.049)和TNM分期(P=0.041)有关;多重逐步回归分析结果显示,血管浸润(P=0.013)和TNM分期(P=0.024)是影响CDKL5m RNA表达的重要因素;胃癌组织和细胞株中CDKL5蛋白除了在相对分子质量为107×103条带处显影外,还检测到在相对分子质量为85×103处的显影条带。结论 CDKL5在胃癌组织和细胞中均呈高表达,其m RNA表达与胃癌患者的血管浸润和TNM分期有关;CDKL5蛋白分别在相对分子质量为107×103和85×103条带处显影,提示CDKL5在蛋白水平可能存在不同的修饰方式或者表达方式。展开更多
基金supported by the National Natural Science Foundation of China(82173796).Ava。
文摘Developmental and epileptic encephalopathies are severe neurological conditions in clinical practice,among which loss-of-function mutations in brain-enriched serine-threonine kinase cyclin dependent kinase like-5(CDKL5)exists as one of the most common types.It is unknown,therefore,how precisely CDKL5 mutations lead to neuronal hyper-excitation.A recent study that looked at the connection between voltage-gated calcium channel Cav2.3 and CDKL5 in an experimental context was published in Nature Communications.This study has revealed that Cav2.3,a physi-ological phosphorylation target of CDKL5,would show delayed inactivation and increased cholinergic stimulation in CDKL5 knock out conditions.This would in turn cause neuronal hyperexcitability and related enhanced seizure susceptibility.This work,in our opinion,provided fresh insight into the epileptic encephalopathies linked to CDKL5 and highlighted Cav2.3 as a possible target for it.
文摘BACKGROUND： The discovery that mutations in cyclin-dependent kinase-like 5 （CDKLS） gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular and genetic basis of CDKL5 disorder. Given the large number of literature published thus far, this review aims to summarize current genetic studies, draw a consensus on proposed molecular functions, and point to gaps of knowledge in CDKL5 research. METHODS： A systematic review process was conducted using the PubMed search engine focusing on CDKL5 studies in the recent ten years. We analyzed these publications and summarized the findings into four sections： genetic studies, CDKL5 expression patterns, molecular functions, and animal models. We also discussed challenges and future directions in each section. RESULTS： On the clinical side, CDKL5 disorder is characterized by early onset epileptic seizures, intellectual disability, and stereotypical behaviors. On the research side, a series of molecular and genetic studies in human patients, cell cultures and animal models have established the causality of CDKL5 to the infantile epileptic encephalopathy, and pointed to a key role for CDKL5 in regulating neuronal function in the brain. Mouse models of CDKL5 disorder have also been developed, and notably, manifest behavioral phenotypes, mimicking numerous clinical symptoms of CDKL5 disorder and advancing CDKL5 research to the preclinical stage. CONCLUSIONS： Given what we have learned thus far, future identification of robust, quantitative, and sensitive outcome measures would be the key in animal model studies, particularly in heterozygous females. In the meantime, molecular and cellular studies of CDKL5 should focus on mechanism-based investigation and aim to uncover druggable targets that offer the potential to rescue or ameliorate CDKL5 disorder-related phenotypes.
文摘目的研究丝/苏氨酸激酶周期素依赖性激酶样-5(CDKL5)在胃癌组织中的表达,并分析其与胃癌患者的临床病理特征之间的关系。方法应用荧光实时定量PCR法和免疫印迹法分别检测45例胃癌及其癌旁组织中CDKL5 m RNA及蛋白的表达,然后用免疫荧光方法检测CDKL5蛋白在AGS和MKN-45胃癌细胞株中的表达情况。结果 CDKL5 m RNA和蛋白在胃癌组织中的表达均明显高于其在相应的癌旁组织中的表达(P<0.05);CDKL5 m RNA的表达与胃癌患者的年龄(P=0.033)、血管浸润(P=0.007)、T分期(P=0.049)和TNM分期(P=0.041)有关;多重逐步回归分析结果显示,血管浸润(P=0.013)和TNM分期(P=0.024)是影响CDKL5m RNA表达的重要因素;胃癌组织和细胞株中CDKL5蛋白除了在相对分子质量为107×103条带处显影外,还检测到在相对分子质量为85×103处的显影条带。结论 CDKL5在胃癌组织和细胞中均呈高表达,其m RNA表达与胃癌患者的血管浸润和TNM分期有关;CDKL5蛋白分别在相对分子质量为107×103和85×103条带处显影,提示CDKL5在蛋白水平可能存在不同的修饰方式或者表达方式。
