CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions
DNA damage, which perturbs genomic stability, has been linked to cognitive decline in the aging human brain, and mutations in DNA repair genes have neurological implications. Several studies have suggested that DNA damage is also increased in brain disorders such as Alzheimer's disease, Parkins...
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2014
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01674889_v1843_n7_p1309_Ogara http://hdl.handle.net/20.500.12110/paper_01674889_v1843_n7_p1309_Ogara |
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paper:paper_01674889_v1843_n7_p1309_Ogara |
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dspace |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Apoptosis Beta amyloid peptide DNA damage Learning and memory Neocarzinostatin Neurodegeneration calcium cyclin dependent kinase 5 cyclin dependent kinase inhibitor 2D DNA RNA amyloid beta protein amyloid beta-protein (25-35) calcium Cdk5 protein, mouse Cdkn2d protein, mouse cyclin dependent kinase 5 cyclin dependent kinase inhibitor 2D cytotoxin peptide fragment zinostatin animal cell animal experiment animal model apoptosis article calcium cell level cell survival cognitive defect controlled study DNA damage DNA repair embryo female genotoxicity hippocampal neuronal culture hippocampus human human cell in vivo study male mouse nerve degeneration neurofeedback nonhuman priority journal protein expression protein phosphorylation protein stability rat animal cognition cytology DNA damage drug effects feedback system gene expression regulation genetic transcription genetics hippocampus metabolism nerve cell phosphorylation physiology primary cell culture signal transduction tumor cell line Amyloid beta-Peptides Animals Apoptosis Calcium Cell Line, Tumor Cell Survival Cognition Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinase Inhibitor p19 Cytotoxins DNA Damage DNA Repair Feedback, Physiological Gene Expression Regulation Hippocampus Humans Mice Neurons Peptide Fragments Phosphorylation Primary Cell Culture Signal Transduction Transcription, Genetic Zinostatin |
| spellingShingle |
Apoptosis Beta amyloid peptide DNA damage Learning and memory Neocarzinostatin Neurodegeneration calcium cyclin dependent kinase 5 cyclin dependent kinase inhibitor 2D DNA RNA amyloid beta protein amyloid beta-protein (25-35) calcium Cdk5 protein, mouse Cdkn2d protein, mouse cyclin dependent kinase 5 cyclin dependent kinase inhibitor 2D cytotoxin peptide fragment zinostatin animal cell animal experiment animal model apoptosis article calcium cell level cell survival cognitive defect controlled study DNA damage DNA repair embryo female genotoxicity hippocampal neuronal culture hippocampus human human cell in vivo study male mouse nerve degeneration neurofeedback nonhuman priority journal protein expression protein phosphorylation protein stability rat animal cognition cytology DNA damage drug effects feedback system gene expression regulation genetic transcription genetics hippocampus metabolism nerve cell phosphorylation physiology primary cell culture signal transduction tumor cell line Amyloid beta-Peptides Animals Apoptosis Calcium Cell Line, Tumor Cell Survival Cognition Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinase Inhibitor p19 Cytotoxins DNA Damage DNA Repair Feedback, Physiological Gene Expression Regulation Hippocampus Humans Mice Neurons Peptide Fragments Phosphorylation Primary Cell Culture Signal Transduction Transcription, Genetic Zinostatin Ogara, Maria Florencia De La Fuente, Veronica Sonzogni, Silvina Verónica Marazita, Mariela C. Cánepa, Eduardo Tomás CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions |
| topic_facet |
Apoptosis Beta amyloid peptide DNA damage Learning and memory Neocarzinostatin Neurodegeneration calcium cyclin dependent kinase 5 cyclin dependent kinase inhibitor 2D DNA RNA amyloid beta protein amyloid beta-protein (25-35) calcium Cdk5 protein, mouse Cdkn2d protein, mouse cyclin dependent kinase 5 cyclin dependent kinase inhibitor 2D cytotoxin peptide fragment zinostatin animal cell animal experiment animal model apoptosis article calcium cell level cell survival cognitive defect controlled study DNA damage DNA repair embryo female genotoxicity hippocampal neuronal culture hippocampus human human cell in vivo study male mouse nerve degeneration neurofeedback nonhuman priority journal protein expression protein phosphorylation protein stability rat animal cognition cytology DNA damage drug effects feedback system gene expression regulation genetic transcription genetics hippocampus metabolism nerve cell phosphorylation physiology primary cell culture signal transduction tumor cell line Amyloid beta-Peptides Animals Apoptosis Calcium Cell Line, Tumor Cell Survival Cognition Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinase Inhibitor p19 Cytotoxins DNA Damage DNA Repair Feedback, Physiological Gene Expression Regulation Hippocampus Humans Mice Neurons Peptide Fragments Phosphorylation Primary Cell Culture Signal Transduction Transcription, Genetic Zinostatin |
| description |
DNA damage, which perturbs genomic stability, has been linked to cognitive decline in the aging human brain, and mutations in DNA repair genes have neurological implications. Several studies have suggested that DNA damage is also increased in brain disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the precise mechanisms connecting DNA damage with neurodegeneration remain poorly understood. CDK5, a critical enzyme in the development of the central nervous system, phosphorylates a number of synaptic proteins and regulates dendritic spine morphogenesis, synaptic plasticity and learning. In addition to these physiological roles, CDK5 has been involved in the neuronal death initiated by DNA damage. We hypothesized that p19INK4d, a member of the cell cycle inhibitor family INK4, is involved in a neuroprotective mechanism activated in response to DNA damage. We found that in response to genotoxic injury or increased levels of intracellular calcium, p19INK4d is transcriptionally induced and phosphorylated by CDK5 which provides it with greater stability in postmitotic neurons. p19INK4d expression improves DNA repair, decreases apoptosis and increases neuronal survival under conditions of genotoxic stress. Our in vivo experiments showed that decreased levels of p19INK4d rendered hippocampal neurons more sensitive to genotoxic insult resulting in the loss of cognitive abilities that rely on the integrity of this brain structure. We propose a feedback mechanism by which the neurotoxic effects of CDK5-p25 activated by genotoxic stress or abnormal intracellular calcium levels are counteracted by the induction and stabilization of p19INK4d protein reducing the adverse consequences on brain functions. © 2014 Elsevier B.V. |
| author |
Ogara, Maria Florencia De La Fuente, Veronica Sonzogni, Silvina Verónica Marazita, Mariela C. Cánepa, Eduardo Tomás |
| author_facet |
Ogara, Maria Florencia De La Fuente, Veronica Sonzogni, Silvina Verónica Marazita, Mariela C. Cánepa, Eduardo Tomás |
| author_sort |
Ogara, Maria Florencia |
| title |
CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions |
| title_short |
CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions |
| title_full |
CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions |
| title_fullStr |
CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions |
| title_full_unstemmed |
CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions |
| title_sort |
cdk5-mediated phosphorylation of p19ink4d avoids dna damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions |
| publishDate |
2014 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01674889_v1843_n7_p1309_Ogara http://hdl.handle.net/20.500.12110/paper_01674889_v1843_n7_p1309_Ogara |
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AT ogaramariaflorencia cdk5mediatedphosphorylationofp19ink4davoidsdnadamageinducedneurodegenerationinmousehippocampusandpreventslossofcognitivefunctions AT delafuenteveronica cdk5mediatedphosphorylationofp19ink4davoidsdnadamageinducedneurodegenerationinmousehippocampusandpreventslossofcognitivefunctions AT sonzognisilvinaveronica cdk5mediatedphosphorylationofp19ink4davoidsdnadamageinducedneurodegenerationinmousehippocampusandpreventslossofcognitivefunctions AT marazitamarielac cdk5mediatedphosphorylationofp19ink4davoidsdnadamageinducedneurodegenerationinmousehippocampusandpreventslossofcognitivefunctions AT canepaeduardotomas cdk5mediatedphosphorylationofp19ink4davoidsdnadamageinducedneurodegenerationinmousehippocampusandpreventslossofcognitivefunctions |
| _version_ |
1768543463855357952 |
| spelling |
paper:paper_01674889_v1843_n7_p1309_Ogara2023-06-08T15:16:29Z CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions Ogara, Maria Florencia De La Fuente, Veronica Sonzogni, Silvina Verónica Marazita, Mariela C. Cánepa, Eduardo Tomás Apoptosis Beta amyloid peptide DNA damage Learning and memory Neocarzinostatin Neurodegeneration calcium cyclin dependent kinase 5 cyclin dependent kinase inhibitor 2D DNA RNA amyloid beta protein amyloid beta-protein (25-35) calcium Cdk5 protein, mouse Cdkn2d protein, mouse cyclin dependent kinase 5 cyclin dependent kinase inhibitor 2D cytotoxin peptide fragment zinostatin animal cell animal experiment animal model apoptosis article calcium cell level cell survival cognitive defect controlled study DNA damage DNA repair embryo female genotoxicity hippocampal neuronal culture hippocampus human human cell in vivo study male mouse nerve degeneration neurofeedback nonhuman priority journal protein expression protein phosphorylation protein stability rat animal cognition cytology DNA damage drug effects feedback system gene expression regulation genetic transcription genetics hippocampus metabolism nerve cell phosphorylation physiology primary cell culture signal transduction tumor cell line Amyloid beta-Peptides Animals Apoptosis Calcium Cell Line, Tumor Cell Survival Cognition Cyclin-Dependent Kinase 5 Cyclin-Dependent Kinase Inhibitor p19 Cytotoxins DNA Damage DNA Repair Feedback, Physiological Gene Expression Regulation Hippocampus Humans Mice Neurons Peptide Fragments Phosphorylation Primary Cell Culture Signal Transduction Transcription, Genetic Zinostatin DNA damage, which perturbs genomic stability, has been linked to cognitive decline in the aging human brain, and mutations in DNA repair genes have neurological implications. Several studies have suggested that DNA damage is also increased in brain disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. However, the precise mechanisms connecting DNA damage with neurodegeneration remain poorly understood. CDK5, a critical enzyme in the development of the central nervous system, phosphorylates a number of synaptic proteins and regulates dendritic spine morphogenesis, synaptic plasticity and learning. In addition to these physiological roles, CDK5 has been involved in the neuronal death initiated by DNA damage. We hypothesized that p19INK4d, a member of the cell cycle inhibitor family INK4, is involved in a neuroprotective mechanism activated in response to DNA damage. We found that in response to genotoxic injury or increased levels of intracellular calcium, p19INK4d is transcriptionally induced and phosphorylated by CDK5 which provides it with greater stability in postmitotic neurons. p19INK4d expression improves DNA repair, decreases apoptosis and increases neuronal survival under conditions of genotoxic stress. Our in vivo experiments showed that decreased levels of p19INK4d rendered hippocampal neurons more sensitive to genotoxic insult resulting in the loss of cognitive abilities that rely on the integrity of this brain structure. We propose a feedback mechanism by which the neurotoxic effects of CDK5-p25 activated by genotoxic stress or abnormal intracellular calcium levels are counteracted by the induction and stabilization of p19INK4d protein reducing the adverse consequences on brain functions. © 2014 Elsevier B.V. Fil:Ogara, M.F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:de la Fuente, V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Sonzogni, S.V. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Marazita, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Cánepa, E.T. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2014 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01674889_v1843_n7_p1309_Ogara http://hdl.handle.net/20.500.12110/paper_01674889_v1843_n7_p1309_Ogara |