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, 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.
Laboratorio de Biología Molecular, Departamento de Química Biológica, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina.
María Florencia
MF
Ogara
Laboratorio de Biología Molecular, Departamento de Química Biológica, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina.
Laura M
LM
Belluscio
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.
Verónica
V
de la Fuente
Laboratorio de Biología Molecular, Departamento de Química Biológica, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina.
Bruno G
BG
Berardino
Laboratorio de Biología Molecular, Departamento de Química Biológica, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina.
Silvina V
SV
Sonzogni
Laboratorio de Biología Molecular, Departamento de Química Biológica, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina.
Laura
L
Byk
Laboratorio de Biología Molecular, Departamento de Química Biológica, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina.
Mariela
M
Marazita
Laboratorio de Biología Molecular, Departamento de Química Biológica, Ciudad Universitaria, Pabellón II piso 4, 1428 Ciudad de Buenos Aires, Argentina. Electronic address: ecanepa@qb.fcen.uba.ar.
Eduardo T
ET
Cánepa
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003071:Cognition / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics / Q000378:metabolism*; D003603:Cytotoxins / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D015398:Signal Transduction; D014158:Transcription, Genetic; D009353:Zinostatin / Q000494:pharmacology
D016229:Amyloid beta-Peptides; C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D003603:Cytotoxins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D009353:Zinostatin; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D002118:Calcium
Apoptosis; Beta amyloid peptide; DNA damage; Learning and memory; Neocarzinostatin; Neurodegeneration