Role of Cyclin A2 In Aging Hippocampus And rRna Dynamics

Abstract

BackgroundNovel functions of cyclin A2 (CCNA2) have been demonstrated including DNA synthesis initiation and progression, DNA repair, and protein translation through RNA binding. Previously, we reported that loss of CCNA2 leads to hippocampal defects characterized by abnormal DNA repair and impaired performance on behavioral tests due to memory and learning deficits. Abnormalities in RNA processing and synaptic plasticity are mechanisms associated with deficits in memory and aging. This study was addressed to investigate effects of cyclin A2 loss on modulation of RNA processing in the hippocampus of aged mice.MethodsAll work involving animals was performed under the auspices of a protocol approved by the Ohio State University Institutional Animal Care and Use Committee. CamkIIα‐cre mice were interbred with CCNA2fl/fl mice to achieve adult ablation of CCNA2 in the hippocampus and cerebral cortex. To evaluate brain morphology, animals were sacrificed at 8 months. After fixed in 4% paraformaldehyde, crysections were obtained at 12 μm. Electron microscopy was performed and number of synapses and polyribosomes were quantified.ResultsUltrastructural analysis of Stratum Moleculare (SM) and Reticulare (SR) in 8mo mices showed a decrease of the synapse density in CamkIIαcre CCNA2 fl/fl mices as compared with control. However, quantity of ribosomes was increased only in SM of the hippocampus in mutant mices. Immunostaining for ribosomal RNA (rRNA) revealed an accumulation of rRNA granules in dentate gyrus and Cornu Ammonis (CA) both regions of the hippocampus. Quantitative analysis resulted an increased rRNA in the SR. To elucidate if mechanisms of translational regulation are modified by the lack of CCNA2 we screened for alterations of 40S ribosomal protein S6 (S6), and translational repressor eukaryotic initiation factor 4E binding protein (ELF4E) and cytoplasmic polyadenylation element binding protein 1 (CPEB1).ConclusionsOur data shows a distinct role for CCNA2 in adult hippocampus in the regulation of synaptic density as well as the prevention of rRNA granule formation. Alterations in RNA dynamics caused by loss of CCNA2 may be implicated in neuronal disorders and neurodegeneration.Support or Funding InformationThis work was sponsored by NIH/NHLBI grants RO1 HL132354This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.