Omais Saad, Jaafar Carine, Ghanem Noël
Department of Biology, American University of Beirut, Beirut, Lebanon.
Front Neurosci. 2018 Mar 9;12:144. doi: 10.3389/fnins.2018.00144. eCollection 2018.
Adult neurogenesis (AN) is an ongoing developmental process that generates newborn neurons in the olfactory bulb (OB) and the hippocampus (Hi) throughout life and significantly contributes to brain plasticity. Adult neural stem and progenitor cells (aNSPCs) are relatively limited in number and fate and are spatially restricted to the subventricular zone (SVZ) and the subgranular zone (SGZ). During AN, the distinct roles played by cell cycle proteins extend beyond cell cycle control and constitute key regulatory mechanisms involved in neuronal maturation and survival. Importantly, aberrant cell cycle re-entry (CCE) in post-mitotic neurons has been strongly linked to the abnormal pathophysiology in rodent models of neurodegenerative diseases with potential implications on the etiology and progression of such diseases in humans. Here, we present an overview of AN in the SVZ-OB and olfactory epithelium (OE) in mice and humans followed by a comprehensive update of the distinct roles played by cell cycle proteins including major tumors suppressor genes in various steps during neurogenesis. We also discuss accumulating evidence underlining a strong link between abnormal cell cycle control, olfactory dysfunction and neurodegeneration in the adult and aging brain. We emphasize that: (1) CCE in post-mitotic neurons due to loss of cell cycle suppression and/or age-related insults as well as DNA damage can anticipate the development of neurodegenerative lesions and protein aggregates, (2) the age-related decline in SVZ and OE neurogenesis is associated with compensatory pro-survival mechanisms in the aging OB which are interestingly similar to those detected in Alzheimer's disease and Parkinson's disease in humans, and (3) the OB represents a well suitable model to study the early manifestation of age-related defects that may eventually progress into the formation of neurodegenerative lesions and, possibly, spread to the rest of the brain. Such findings may provide a novel approach to the modeling of neurodegenerative diseases in humans from early detection to progression and treatment as well.
成体神经发生（AN）是一个持续的发育过程，一生中在嗅球（OB）和海马体（Hi）中产生新生神经元，并对大脑可塑性有显著贡献。成体神经干细胞和祖细胞（aNSPCs）数量和命运相对有限，在空间上局限于脑室下区（SVZ）和颗粒下区（SGZ）。在成体神经发生过程中，细胞周期蛋白所起的独特作用不仅限于细胞周期控制，还构成了参与神经元成熟和存活的关键调节机制。重要的是，有丝分裂后神经元中异常的细胞周期重新进入（CCE）与神经退行性疾病啮齿动物模型中的异常病理生理学密切相关，这可能对人类此类疾病的病因和进展有潜在影响。在此，我们概述了小鼠和人类中SVZ - OB和嗅上皮（OE）中的成体神经发生，随后全面更新了细胞周期蛋白在神经发生各个步骤中所起的独特作用，包括主要肿瘤抑制基因。我们还讨论了越来越多的证据，强调成年和衰老大脑中异常细胞周期控制、嗅觉功能障碍和神经退行性变之间的紧密联系。我们强调：（1）由于细胞周期抑制丧失和/或与年龄相关的损伤以及DNA损伤导致的有丝分裂后神经元中的CCE可预示神经退行性病变和蛋白质聚集体的发展，（2）SVZ和OE神经发生与年龄相关的下降与衰老OB中的代偿性促存活机制相关，有趣的是，这些机制与在人类阿尔茨海默病和帕金森病中检测到的机制相似，（3）OB是研究可能最终发展为神经退行性病变并可能扩散到大脑其他部位的与年龄相关缺陷早期表现的合适模型。这些发现可能为从早期检测到进展和治疗的人类神经退行性疾病建模提供一种新方法。
