Glial cell line-derived neurotrophic factor(GDNF)plays an important role in the protection of dopaminergic neurons,but there are few reports of the relationship between GDNF and its precursors(α-pro-GDNF andβ-pro-GD...Glial cell line-derived neurotrophic factor(GDNF)plays an important role in the protection of dopaminergic neurons,but there are few reports of the relationship between GDNF and its precursors(α-pro-GDNF andβ-pro-GDNF)and cognitive impairment in Parkinson’s disease.This study aimed to investigate the relationship between the serum levels of GDNF and its precursors and cognitive impairment in Parkinson’s disease,and to assess their potential as a diagnostic marker.Fifty-three primary outpatients and hospitalized patients with Parkinson’s disease(23 men and 30 women)with an average age of 66.58 years were enrolled from the Affiliated Hospital of Xuzhou Medical University of China in this case-control study.The patients were divided into the Parkinson’s disease with cognitive impairment group(n=27)and the Parkinson’s disease with normal cognitive function group(n=26)based on their Mini-Mental State Examination,Montreal Cognitive Assessment,and Clinical Dementia Rating scores.In addition,26 age-and sex-matched healthy subjects were included as the healthy control group.Results demonstrated that serum GDNF levels were significantly higher in the Parkinson’s disease with normal cognitive function group than in the other two groups.There were no significant differences in GDNF precursor levels among the three groups.Correlation analysis revealed that serum GDNF levels,GDNF/α-pro-GDNF ratios,and GDNF/β-pro-GDNF ratios were moderately or highly correlated with the Mini-Mental State Examination,Montreal Cognitive Assessment,and Clinical Dementia Rating scores.To explore the risk factors for cognitive impairment in patients with Parkinson’s disease,logistic regression analysis and stepwise linear regression analysis were performed.Both GDNF levels and Hoehn-Yahr stage were risk factors for cognitive impairment in Parkinson’s disease,and were the common influencing factors for cognitive scale scores.Neitherα-pro-GDNF norβ-pro-GDNF was risk factors for cognitive impairment in Parkinson’s disease.A receiver operating characteristic curve of GDNF was generated to predict cognitive function in Parkinson’s disease(area under the curve=0.859).This result indicates that the possibility that serum GDNF can correctly distinguish whether patients with Parkinson’s disease have cognitive impairment is 0.859.Together,these results suggest that serum GDNF may be an effective diagnostic marker for cognitive impairment in Parkinson’s disease.However,α-pro-GDNF andβ-pro-GDNF are not useful for predicting cognitive impairment in this disease.This study was approved by Ethics Committee of the Affiliated Hospital of Xuzhou Medical University,China(approval No.XYFY2017-KL047-01)on November 30,2017.展开更多
Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relations...Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease.展开更多
Pitx3 is strongly associated with the phenotype, differentiation, and survival of dopaminergic neurons. The relationship between Pitx3 and glial cell line-derived neurotrophic factor（GDNF） in dopaminergic neurons re...Pitx3 is strongly associated with the phenotype, differentiation, and survival of dopaminergic neurons. The relationship between Pitx3 and glial cell line-derived neurotrophic factor（GDNF） in dopaminergic neurons remains poorly understood. The present investigation sought to construct and screen a lentivirus expression plasmid carrying a rat Pitx3 short hairpin（sh）RNA and to assess the impact of Pitx3 gene knockdown on GDNF transcriptional activity in MES23.5 dopaminergic neurons. Three pairs of interference sequences were designed and separately ligated into GV102 expression vectors. These recombinant plasmids were transfected into MES23.5 cells and western blot assays were performed to detect Pitx3 protein expression. Finally, the most effective Pitx3 sh RNA and a dual-luciferase reporter gene plasmid carrying the GDNF promoter region（GDNF-luciferase） were cotransfected into MES23.5 cells. Sequencing showed that the synthesized sequences were identical to the three Pitx3 interference sequences. Inverted fluorescence microscopy revealed that the lentivirus expression plasmids carrying Pitx3-sh RNA had 40-50% transfection efficiency. Western blot assay confirmed that the corresponding Pitx3 of the third knockdown sequence had the lowest expression level. Dual-luciferase reporter gene results showed that the GDNF transcriptional activity in dopaminergic cells cotransfected with both plasmids was decreased compared with those transfected with GDNF-luciferase alone. Together, the results showed that the designed Pitx3-sh RNA interference sequence decreased Pitx3 protein expression, which decreased GDNF transcriptional activity.展开更多
基金This work was funded by the National Natural Science Foundation of China,No.81971006(to DSG)the Postgraduate Research and Practice Innovation Program of Jiangsu Province of China,Nos.KYCX18_2193(to MYS),KYCX18_2171(to CXT).
文摘Glial cell line-derived neurotrophic factor(GDNF)plays an important role in the protection of dopaminergic neurons,but there are few reports of the relationship between GDNF and its precursors(α-pro-GDNF andβ-pro-GDNF)and cognitive impairment in Parkinson’s disease.This study aimed to investigate the relationship between the serum levels of GDNF and its precursors and cognitive impairment in Parkinson’s disease,and to assess their potential as a diagnostic marker.Fifty-three primary outpatients and hospitalized patients with Parkinson’s disease(23 men and 30 women)with an average age of 66.58 years were enrolled from the Affiliated Hospital of Xuzhou Medical University of China in this case-control study.The patients were divided into the Parkinson’s disease with cognitive impairment group(n=27)and the Parkinson’s disease with normal cognitive function group(n=26)based on their Mini-Mental State Examination,Montreal Cognitive Assessment,and Clinical Dementia Rating scores.In addition,26 age-and sex-matched healthy subjects were included as the healthy control group.Results demonstrated that serum GDNF levels were significantly higher in the Parkinson’s disease with normal cognitive function group than in the other two groups.There were no significant differences in GDNF precursor levels among the three groups.Correlation analysis revealed that serum GDNF levels,GDNF/α-pro-GDNF ratios,and GDNF/β-pro-GDNF ratios were moderately or highly correlated with the Mini-Mental State Examination,Montreal Cognitive Assessment,and Clinical Dementia Rating scores.To explore the risk factors for cognitive impairment in patients with Parkinson’s disease,logistic regression analysis and stepwise linear regression analysis were performed.Both GDNF levels and Hoehn-Yahr stage were risk factors for cognitive impairment in Parkinson’s disease,and were the common influencing factors for cognitive scale scores.Neitherα-pro-GDNF norβ-pro-GDNF was risk factors for cognitive impairment in Parkinson’s disease.A receiver operating characteristic curve of GDNF was generated to predict cognitive function in Parkinson’s disease(area under the curve=0.859).This result indicates that the possibility that serum GDNF can correctly distinguish whether patients with Parkinson’s disease have cognitive impairment is 0.859.Together,these results suggest that serum GDNF may be an effective diagnostic marker for cognitive impairment in Parkinson’s disease.However,α-pro-GDNF andβ-pro-GDNF are not useful for predicting cognitive impairment in this disease.This study was approved by Ethics Committee of the Affiliated Hospital of Xuzhou Medical University,China(approval No.XYFY2017-KL047-01)on November 30,2017.
基金supported by the National Natural Science Foundation of China,Nos. 81971006 (to DSG), 82101263 (to CXT)Jiangsu Province Science Foundation for Youths,No. BK20210903 (to CXT)+2 种基金Research Foundation for Talented Scholars of Xuzhou Medical University,No. RC20552114 (to CXT)Science&Technology Program of Xuzhou,No. KC19016 (to JC)Project of Xuzhou Medical University,No. 2018KJ06 (to JC)。
文摘Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease.
基金supported by the National Natural Science Foundation of China,No.81372698
文摘Pitx3 is strongly associated with the phenotype, differentiation, and survival of dopaminergic neurons. The relationship between Pitx3 and glial cell line-derived neurotrophic factor（GDNF） in dopaminergic neurons remains poorly understood. The present investigation sought to construct and screen a lentivirus expression plasmid carrying a rat Pitx3 short hairpin（sh）RNA and to assess the impact of Pitx3 gene knockdown on GDNF transcriptional activity in MES23.5 dopaminergic neurons. Three pairs of interference sequences were designed and separately ligated into GV102 expression vectors. These recombinant plasmids were transfected into MES23.5 cells and western blot assays were performed to detect Pitx3 protein expression. Finally, the most effective Pitx3 sh RNA and a dual-luciferase reporter gene plasmid carrying the GDNF promoter region（GDNF-luciferase） were cotransfected into MES23.5 cells. Sequencing showed that the synthesized sequences were identical to the three Pitx3 interference sequences. Inverted fluorescence microscopy revealed that the lentivirus expression plasmids carrying Pitx3-sh RNA had 40-50% transfection efficiency. Western blot assay confirmed that the corresponding Pitx3 of the third knockdown sequence had the lowest expression level. Dual-luciferase reporter gene results showed that the GDNF transcriptional activity in dopaminergic cells cotransfected with both plasmids was decreased compared with those transfected with GDNF-luciferase alone. Together, the results showed that the designed Pitx3-sh RNA interference sequence decreased Pitx3 protein expression, which decreased GDNF transcriptional activity.
