Maiese Kenneth
Cellular and Molecular Signaling, Newark, New Jersey 07101, United States.
Curr Neurovasc Res. 2017;14(4):415-420. doi: 10.2174/1567202614666171116102911.
With almost 47 million individuals worldwide suffering from some aspect of dementia, it is clear that cognitive loss impacts a significant proportion of the global population. Unfortunately, definitive treatments to resolve or prevent the onset of cognitive loss are limited. In most cases such care is currently non-existent prompting the need for novel treatment strategies.
Mammalian forkhead transcription factors of the O class (FoxO) are one such avenue of investigation that offer an exciting potential to bring new treatments forward for disorders that involve cognitive loss. Here we examine the background, structure, expression, and function of FoxO transcription factors and their role in cognitive loss, programmed cell death in the nervous system with apoptosis and autophagy, and areas to target FoxOs for dementia and specific disorders such as Alzheimer's disease.
FoxO proteins work in concert with a number of other cell survival pathways that involve growth factors, such as erythropoietin and neurotrophins, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), Wnt signaling, and cancer-related pathways. FoxO transcription factors oversee proinflammatory pathways, affect nervous system amyloid (Aβ) production and toxicity, lead to mitochondrial dysfunction, foster neuronal apoptotic cell death, and accelerate the progression of degenerative disease. However, under some scenarios such as those involving autophagy, FoxOs also can offer protection in the nervous system and reduce toxic intracellular protein accumulations and potentially limit Aβ toxicity.
Given the ability of FoxOs to not only promote apoptotic cell death in the nervous system, but also through the induction of autophagy offer protection against degenerative disease that can lead to dementia, a fine balance in the activity of FoxOs may be required to target cognitive loss in individuals. Future work should yield exciting new prospects for FoxO proteins as new targets to treat the onset and progression of cognitive loss and dementia.
全球近4700万人患有某种形式的痴呆症，显然认知能力丧失影响着全球相当大比例的人口。不幸的是，解决或预防认知能力丧失的确定性治疗方法有限。在大多数情况下，目前尚无此类治疗方法，这促使人们需要新的治疗策略。
O类哺乳动物叉头转录因子（FoxO）是一种研究途径，为涉及认知能力丧失的疾病带来新治疗方法提供了令人兴奋的潜力。在此，我们研究FoxO转录因子的背景、结构、表达和功能，及其在认知能力丧失、神经系统中通过凋亡和自噬进行的程序性细胞死亡中的作用，以及针对痴呆症和特定疾病（如阿尔茨海默病）靶向FoxO的领域。
FoxO蛋白与许多其他涉及生长因子的细胞存活途径协同作用，如促红细胞生成素和神经营养因子、沉默交配型信息调节2同源物1（酿酒酵母）（SIRT1）、Wnt1诱导信号通路蛋白1（WISP1）、Wnt信号通路和癌症相关通路。FoxO转录因子监督促炎途径，影响神经系统淀粉样蛋白（Aβ）的产生和毒性，导致线粒体功能障碍，促进神经元凋亡性细胞死亡，并加速退行性疾病的进展。然而，在某些情况下，如涉及自噬的情况，FoxO也可以在神经系统中提供保护，减少细胞内有毒蛋白质的积累，并可能限制Aβ毒性。
鉴于FoxO不仅能够促进神经系统中的凋亡性细胞死亡，还能通过诱导自噬提供针对可导致痴呆症的退行性疾病保护，可能需要在FoxO的活性中保持精细平衡以针对个体的认知能力丧失。未来的工作应为FoxO蛋白作为治疗认知能力丧失和痴呆症的发生与进展的新靶点带来令人兴奋的新前景。
