Artículo

Ogara, M.F.; Belluscio, L.M.; de la Fuente, V.; Berardino, B.G.; Sonzogni, S.V.; Byk, L.; Marazita, M.; Cánepa, E.T. "CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions" (2014) Biochimica et Biophysica Acta - Molecular Cell Research. 1843(7):1309-1324
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Abstract:

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.

Registro:

Documento: Artículo
Título:CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions
Autor:Ogara, M.F.; Belluscio, L.M.; de la Fuente, V.; Berardino, B.G.; Sonzogni, S.V.; Byk, L.; Marazita, M.; Cánepa, E.T.
Filiación:Laboratorio de Biología Molecular, Departamento de Química Biológica, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina
Laboratorio de Neurobiología de la Memoria, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina
Palabras clave: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
Año:2014
Volumen:1843
Número:7
Página de inicio:1309
Página de fin:1324
DOI: http://dx.doi.org/10.1016/j.bbamcr.2014.03.026
Título revista:Biochimica et Biophysica Acta - Molecular Cell Research
Título revista abreviado:Biochim. Biophys. Acta Mol. Cell Res.
ISSN:01674889
CODEN:BAMRD
CAS:calcium, 7440-70-2, 14092-94-5; DNA, 9007-49-2; RNA, 63231-63-0; amyloid beta protein, 109770-29-8; zinostatin, 9014-02-2; Amyloid beta-Peptides; amyloid beta-protein (25-35); Calcium; Cdk5 protein, mouse; Cdkn2d protein, mouse; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinase Inhibitor p19; Cytotoxins; Peptide Fragments; Zinostatin
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01674889_v1843_n7_p1309_Ogara

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Citas:

---------- APA ----------
Ogara, M.F., Belluscio, L.M., de la Fuente, V., Berardino, B.G., Sonzogni, S.V., Byk, L., Marazita, M.,..., Cánepa, E.T. (2014) . CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions. Biochimica et Biophysica Acta - Molecular Cell Research, 1843(7), 1309-1324.
http://dx.doi.org/10.1016/j.bbamcr.2014.03.026
---------- CHICAGO ----------
Ogara, M.F., Belluscio, L.M., de la Fuente, V., Berardino, B.G., Sonzogni, S.V., Byk, L., et al. "CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions" . Biochimica et Biophysica Acta - Molecular Cell Research 1843, no. 7 (2014) : 1309-1324.
http://dx.doi.org/10.1016/j.bbamcr.2014.03.026
---------- MLA ----------
Ogara, M.F., Belluscio, L.M., de la Fuente, V., Berardino, B.G., Sonzogni, S.V., Byk, L., et al. "CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions" . Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1843, no. 7, 2014, pp. 1309-1324.
http://dx.doi.org/10.1016/j.bbamcr.2014.03.026
---------- VANCOUVER ----------
Ogara, M.F., Belluscio, L.M., de la Fuente, V., Berardino, B.G., Sonzogni, S.V., Byk, L., et al. CDK5-mediated phosphorylation of p19INK4d avoids DNA damage-induced neurodegeneration in mouse hippocampus and prevents loss of cognitive functions. Biochim. Biophys. Acta Mol. Cell Res. 2014;1843(7):1309-1324.
http://dx.doi.org/10.1016/j.bbamcr.2014.03.026