Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation...Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation and processing of proteins,mitochondrial dysfunction,and oxidative stress leading to apoptotic death.However,a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration.The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms,including c-Jun N-terminal kinases,p38 mitogen-activated protein kinases,and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades;post-translational modifications such as Tau-phosphorylation;and DNA damage response.In all these events,implicated Cdk5,a proline-directed serine/threonine protein kinase,seems to be responsible for several cellular processes in neurons including axon growth,neurotransmission,synaptic plasticity,neuronal migration,and maintenance of neuronal survival.However,under pathological conditions,Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons.Thus,Cdk5 hyperactivation,by its physiologic activator p25,hyper-phosphorylates downstream substrates related to neurodegenerative diseases.This review summarizes factors such as oxidative stress,DNA damage response,signaling pathway disturbance,and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons.It also describes how all these factors are linked to a greater or lesser extent with Cdk5.Thus,it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease by cell cycle activation.展开更多
AIM To evaluate the predictive value of the expression of chromosomal maintenance(CRM)1 and cyclindependent kinase(CDK)5 in gastric cancer(GC) patients after gastrectomy.METHODS A total of 240 GC patients who received...AIM To evaluate the predictive value of the expression of chromosomal maintenance(CRM)1 and cyclindependent kinase(CDK)5 in gastric cancer(GC) patients after gastrectomy.METHODS A total of 240 GC patients who received standard gastrectomy were enrolled in the study. The expression level of CRM1 and CDK5 was detected by immunohistochemistry. The correlations between CRM1 and CDK5 expression and clinicopathological factors were explored. Univariate and multivariate survival analyses were used to identify prognostic factors for GC. Receiver operating characteristic analysis was used to compare the accuracy of the prediction of clinical outcome by the parameters. RESULTS The expression of CRM1 was significantly related to size of primary tumor(P = 0.005), Borrmann type(P = 0.006), degree of differentiation(P = 0.004), depth of invasion(P = 0.008), lymph node metastasis(P = 0.013), TNM stage(P = 0.002) and distant metastasis(P = 0.015). The expression of CDK5 was significantly related to sex(P = 0.048) and Lauren's classification(P = 0.011). Multivariate Cox regression analysis identified that CRM1 and CDK5 co-expression status was an independent prognostic factor for overall survival(OS) of patients with GC. Integration of CRM1 and CDK5 expression could provide additional prognostic value for OS compared with CRM1 or CDK5 expression alone(P = 0.001).CONCLUSION CRM1 and CDK5 co-expression was an independent prognostic factors for GC. Combined CRM1 and CDK5 expression could provide a prognostic model for OS of GC.展开更多
Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors.However,the molecular mechanisms underlying this disturbance rem...Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors.However,the molecular mechanisms underlying this disturbance remain elusive.Here,we showed that cyclin-dependent kinase 5(Cdk5)was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis.Serum levels of CDK5 also decreased in patients with Parkinson’s disease accompanied by motor symptoms.Moreover,Cdk5 deficiency in cholinergic neurons triggered paw tremors,abnormal motor coordination,and motor balance deficits in mice.These symptoms occurred along with cholinergic neuron hyperexcitability and increases in the current density of large-conductance Ca2+-activated K+channels(BK channels).Pharmacological inhibition of BK channels restrained the excessive intrinsic excitability of striatal cholinergic neurons in Cdk5-deficient mice.Furthermore,CDK5 interacted with BK channels and negatively regulated BK channel activity via phosphorylation of threonine-908.Restoration of CDK5 expression in striatal cholinergic neurons reduced dyskinesia-like behaviors in ChAT-Cre;Cdk5f/f mice.Together,these findings indicate that CDK5-induced phosphorylation of BK channels involves in cholinergic-neuronmediated motor function,providing a potential new therapeutic target for treating dyskinesia-like behaviors arising from neurological diseases.展开更多
基金supported by the Spanish Ministry of Industry and Competitiveness[Grant BFU2016-80006-P]The Andalusian Regional Government[Group BIO-216]the FEDER-Andalusian programme 2014-2020[1262530-R].
文摘Neurodegenerative diseases are caused by the progressive loss of specific neurons.The exact mechanisms of action of these diseases are unknown,and many studies have focused on pathways related to abnormal accumulation and processing of proteins,mitochondrial dysfunction,and oxidative stress leading to apoptotic death.However,a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration.The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms,including c-Jun N-terminal kinases,p38 mitogen-activated protein kinases,and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades;post-translational modifications such as Tau-phosphorylation;and DNA damage response.In all these events,implicated Cdk5,a proline-directed serine/threonine protein kinase,seems to be responsible for several cellular processes in neurons including axon growth,neurotransmission,synaptic plasticity,neuronal migration,and maintenance of neuronal survival.However,under pathological conditions,Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons.Thus,Cdk5 hyperactivation,by its physiologic activator p25,hyper-phosphorylates downstream substrates related to neurodegenerative diseases.This review summarizes factors such as oxidative stress,DNA damage response,signaling pathway disturbance,and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons.It also describes how all these factors are linked to a greater or lesser extent with Cdk5.Thus,it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and Huntington’s disease by cell cycle activation.
基金Supported by National Natural Science Foundation of China,No.81441123(to Huang CM),No.31640053(to Lin Y)National Key Clinical Specialty Discipline Construction Program of China,No.[2012]649+1 种基金Key Scientific and Technological Project of Fujian Province,China,No.2014Y0025(to Huang CM)Natural Science Foundation of Fujian Province,China,No.2014J01322(to Xie JW),No.2016Y0029(to Lin Y)
文摘AIM To evaluate the predictive value of the expression of chromosomal maintenance(CRM)1 and cyclindependent kinase(CDK)5 in gastric cancer(GC) patients after gastrectomy.METHODS A total of 240 GC patients who received standard gastrectomy were enrolled in the study. The expression level of CRM1 and CDK5 was detected by immunohistochemistry. The correlations between CRM1 and CDK5 expression and clinicopathological factors were explored. Univariate and multivariate survival analyses were used to identify prognostic factors for GC. Receiver operating characteristic analysis was used to compare the accuracy of the prediction of clinical outcome by the parameters. RESULTS The expression of CRM1 was significantly related to size of primary tumor(P = 0.005), Borrmann type(P = 0.006), degree of differentiation(P = 0.004), depth of invasion(P = 0.008), lymph node metastasis(P = 0.013), TNM stage(P = 0.002) and distant metastasis(P = 0.015). The expression of CDK5 was significantly related to sex(P = 0.048) and Lauren's classification(P = 0.011). Multivariate Cox regression analysis identified that CRM1 and CDK5 co-expression status was an independent prognostic factor for overall survival(OS) of patients with GC. Integration of CRM1 and CDK5 expression could provide additional prognostic value for OS compared with CRM1 or CDK5 expression alone(P = 0.001).CONCLUSION CRM1 and CDK5 co-expression was an independent prognostic factors for GC. Combined CRM1 and CDK5 expression could provide a prognostic model for OS of GC.
基金This work was supported by the National Key Research and Development Program of China(2022YFE0108600)the State Key Program of National Natural Science Foundations of China(81930103)the National Natural Science Foundations of China(81973300,82104162,and 82171249).
文摘Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors.However,the molecular mechanisms underlying this disturbance remain elusive.Here,we showed that cyclin-dependent kinase 5(Cdk5)was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis.Serum levels of CDK5 also decreased in patients with Parkinson’s disease accompanied by motor symptoms.Moreover,Cdk5 deficiency in cholinergic neurons triggered paw tremors,abnormal motor coordination,and motor balance deficits in mice.These symptoms occurred along with cholinergic neuron hyperexcitability and increases in the current density of large-conductance Ca2+-activated K+channels(BK channels).Pharmacological inhibition of BK channels restrained the excessive intrinsic excitability of striatal cholinergic neurons in Cdk5-deficient mice.Furthermore,CDK5 interacted with BK channels and negatively regulated BK channel activity via phosphorylation of threonine-908.Restoration of CDK5 expression in striatal cholinergic neurons reduced dyskinesia-like behaviors in ChAT-Cre;Cdk5f/f mice.Together,these findings indicate that CDK5-induced phosphorylation of BK channels involves in cholinergic-neuronmediated motor function,providing a potential new therapeutic target for treating dyskinesia-like behaviors arising from neurological diseases.
