CCNA2 Ablation in Aged Mice Results in Abnormal rRNA Granule Accumulation in Hippocampus

Abstract

Mounting evidence in the literature suggests that RNAeRNA binding protein aggregations can disturb neuronal homeostasis and lead to symptoms associated with normal aging as well as dementia. The specific ablation of cyclin A2 in adult neurons results in neuronal polyribosome aggregations and learning and memory deficits. Detailed histologic and ultrastructural assays of aged mice revealed that post-mitotic hippocampal pyramidal neurons maintain cyclin A2 expression and that proliferative cells in the dentate subgranular zone express cyclin A2. Cyclin A2 loss early during neural development inhibited hippocampal development through canonical/cell-cycle mechanisms, including prolonged cell cycle timing in embryonic hippocampal progenitor cells. However, in mature neurons, cyclin A2 colocalized with dendritic rRNA. Cyclin A2 ablation in adult hippocampus resulted in decreased synaptic density in the hippocampus as well as in accumulation of rRNA granules in dendrite shafts. We conclude that cyclin A2 functions in a noncanonical/nonecell cycle regulatory role to maintain adult pyramidal neuron ribostasis. (Am J Pathol 2019, 189: 426e439; https://doi.

Neuronal RNA granules are ribosome complexes stalled at the pre-translocation state

“…Neuronal RNA granules are morula-like particles Wistar rat cerebral cortex, cerebellum, and hippocampus were used as sources of RNA granule material, as those tissues are involved in various memory-related tasks (Alves et al, 2019;Chen et al, 2017;Costa-Mattioli et al, 2009;Graber et al, 2017;Lebeau et al, 2011;Miyakawa et al, 2001;Nakayama et al, 2017;Ohashi et al, 2016;Shepherd et al, 2006). To reduce contamination from the surrounding glial cells, the tissues were extracted from the brains of postnatal day 0 to 6 rats of both sexes, as gliogenesis starts from postnatal week 2 (Bandeira et al, 2009).…”

“…Localized protein synthesis in neurons is essential for long-term memory formation, and synaptic plasticity (Alves et al, 2019;Chen et al, 2017;Costa-Mattioli et al, 2009;Graber et al, 2017;Lebeau et al, 2011;Miyakawa et al, 2001;Nakayama et al, 2017;Ohashi et al, 2016;Shepherd et al, 2006;Sudhakaran et al, 2014;Weng et al, 2018). Neuronal RNA granules serve as the functional units for transport and translational control (Alami et al, 2014;Gopal et al, 2017;Liao et al, 2019;Sahoo et al, 2018).…”

Alzheimer’s disease-specific cytokine secretion suppresses neuronal mitochondrial metabolism

“…19,44,106 Cdk9 and npm1 are implicated in cell survival, 51,63,67,69 and ccna2 is associated with DNA repair in aging, rRNA homeostasis, and cellular senescence. 3,36,100 The down-regulation of this cluster of genes with treatment suggests increased neuronal and synaptic vulnerability to injury. Strikingly, the neuron network includes a grouping of primarily down-regulated genes involved in mitochondrial respiration, including subunits of every complex involved in the electron transport chain.…”