Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio.
Center for Biostatistics, The Ohio State University College of Medicine, Columbus, Ohio.
Am J Pathol. 2019 Feb;189(2):426-439. doi: 10.1016/j.ajpath.2018.10.020. Epub 2018 Dec 21.
Mounting evidence in the literature suggests that RNA-RNA 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/non-cell cycle regulatory role to maintain adult pyramidal neuron ribostasis.
越来越多的文献证据表明，RNA-RNA 结合蛋白聚集体可能会扰乱神经元的内稳态，并导致与正常衰老以及痴呆相关的症状。在成年神经元中特异性地消除细胞周期蛋白 A2 会导致神经元多核糖体聚集体以及学习和记忆缺陷。对老年小鼠的详细组织学和超微结构分析表明，有丝分裂后海马锥体神经元保持细胞周期蛋白 A2 的表达，而齿状回颗粒下区的增殖细胞表达细胞周期蛋白 A2。神经发育早期细胞周期蛋白 A2 的丢失通过经典/细胞周期机制抑制了海马的发育，包括胚胎海马祖细胞中细胞周期时间的延长。然而，在成熟神经元中，细胞周期蛋白 A2 与树突 rRNA 共定位。成年海马体中细胞周期蛋白 A2 的缺失导致海马体中的突触密度降低，以及树突干中 rRNA 颗粒的积累。我们得出结论，细胞周期蛋白 A2 以非经典/非细胞周期调节的作用方式发挥功能，以维持成年锥体神经元的核糖体稳定性。
