Ishunina Tatjana A
Department of Histology, Embryology and Cytology, Kursk State Medical University, Kursk, Russia.
Handb Clin Neurol. 2021;182:177-189. doi: 10.1016/B978-0-12-819973-2.00012-5.
Human genes show the highest efficacy of alternative splicing (AS) in the brain as compared to other tissues. Within the brain, a remarkably rich diversity of AS events was identified in the hypothalamus. The AS frequency is increased in the aging brain. Such AS events, as intron retention and accumulation of circular RNAs, were acknowledged as some of the main hallmarks of the aging brain. In Alzheimer's disease (AD) pivotal (tau gene, in particular), risk, candidate and other genes show significant alterations in AS. Therefore AD has been suggested to be a disease of dysregulated AS. One of the reported risk factors for AD is estrogen deficiency that may interfere with the extension of neurobrillary tangles. Mounting evidence suggests that estrogens may decrease hyperphosphorylated tau deposition in the brain. Furthermore, AS of estrogen receptor α (ERα) mRNA is decreased in AD brain areas with the highest tau load. These potential interactions among tau, estrogens, and ERα AS may be important for the development of therapeutic and preventive strategies for AD. The intriguing point is that the amount of splice variants of ERα in the hypothalamus and the hippocampus is increased in aging and decreased in AD, while ERα is one of the regulators of AS and is subject to AS itself.
与其他组织相比，人类基因在大脑中表现出最高的可变剪接（AS）效率。在大脑中，下丘脑被发现存在极其丰富多样的AS事件。衰老大脑中的AS频率会增加。诸如内含子保留和环状RNA积累等AS事件被认为是衰老大脑的一些主要特征。在阿尔茨海默病（AD）中，关键基因（特别是tau基因）、风险基因、候选基因和其他基因在AS方面表现出显著变化。因此，AD被认为是一种AS失调的疾病。AD的一个已报道的风险因素是雌激素缺乏，它可能会干扰神经原纤维缠结的扩展。越来越多的证据表明，雌激素可能会减少大脑中过度磷酸化的tau沉积。此外，在tau负荷最高的AD脑区，雌激素受体α（ERα）mRNA的AS减少。tau、雌激素和ERα AS之间的这些潜在相互作用可能对AD治疗和预防策略的制定很重要。有趣的是，下丘脑和海马体中ERα的剪接变体数量在衰老时增加，在AD时减少，而ERα是AS的调节因子之一，其本身也会发生AS。
