中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (2): 320-322.doi: 10.4103/1673-5374.317971

• 观点:脑损伤修复保护与再生 • 上一篇    下一篇

增强蛋白水解途径作为抗糖基化脑损伤的治疗方法？

  

  • 出版日期:2022-02-15 发布日期:2021-10-08

Boosting proteolytic pathways as a treatment against glycation-derived damage in the brain?

Allen Taylor*, Eloy Bejarano*   

  1. Laboratory for Nutrition and Vision Research, USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA (Taylor A, Bejarano E) 
    Departments of Chemical and Molecular Biology and Ophthalmology, Tufts University School of Medicine, Boston, MA, USA (Taylor A)
    Friedman School of Nutrition and Science Policy, Tufts University, Boston, MA, USA (Taylor A)
    School of Health Sciences and Veterinary School, Universidad Cardenal Herrera-CEU, CEU Universities, Moncada, Valencia, Spain (Bejarano E)
  • Online:2022-02-15 Published:2021-10-08
  • Contact: Allen Taylor, PhD, allen.taylor@tufts.edu; Eloy Bejarano, PhD, eloy.bejaranofernandez@uchceu.es.
  • Supported by:
    This work was supported by NIH RO1EY028559, RO1EY026979 (to AT), USDA NIFA 2016–08885 (to AT), USDA 8050-51000-089-01S (to AT), Kamada (to AT), Thome Memorial Foundation (to AT) and a grant from the Human Nutrition Research Center on Aging (to EB). This material is based upon work supported by the US Department of Agriculture—Agricultural Research Service (ARS), under Agreement No. 58-1950-4-003.

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摘要： Neural Regen Res：蛋白水解途径是抵抗大脑糖基化损害的最后一道防线
    外源性高级糖化终产物是指直接摄入食物，消化后释放到血液循环中的高级糖化终产物，由于消化系统吸收效率低，肾脏分泌效率高，仅占人体高级糖化终产物总量的30%。糖基化与血糖浓度成正比，特别是在葡萄糖转运蛋白开放的组织中，如眼睛的大部分部位。防止高级糖化终产物形成的机制包括乙醛酶系统和DJ-1/Park7脱糖酶。抗糖基化活性的效率随着年龄的增长而下降，导致老年人组织中高级糖化终产物加速积累。糖基化应激的一个主要问题是这种非酶过程的不可逆性。避免高级糖化终产物累积和相关组织功能障碍的唯一选择是有效去除高级糖化终产物。高级糖化终产物的积累既取决于生物发生的速率，也取决于蛋白质水解系统去除高级糖化终产物的速率。最新文献表明，泛素-蛋白酶体系统和自噬-溶酶体途径是两种主要的细胞内蛋白水解途径，都有助于有毒糖化蛋白的有效清除。每种途径都可以降解一些高级糖化终产物，它们的活性是互补的。泛素-蛋白酶体系统主要作用于可溶性底物，而自噬可以清除蛋白酶体中不能降解的不溶性底物、聚集体和糖化细胞器。对这些途径的药理学和遗传抑制促进了体外和体内高级糖化终产物的积累，增强的自噬活性减少了高级糖化终产物沉积和高级糖化终产物衍生损伤的发展，如视网膜变性。尽管泛素-蛋白酶体系统和自噬-溶酶体途径在维持高级糖化终产物的稳态水平方面起着协调作用，但是高级糖化终产物随着时间的推移而累积，这是由于这些蛋白水解能力的年龄相关的下降。增强泛素-蛋白酶体系统和自噬-溶酶体途径有利于维持组织的健康。
    来自美国塔夫茨大学的Allen Taylor团队认为，自噬-溶酶体途径是一种细胞内分解代谢过程，介导溶酶体内腔不同生物分子的降解。增强自噬可以改善啮齿动物模型中与衰老相关的神经元退行性变。巨自噬是一种蛋白质水解途径，它吞噬部分胞浆的降解小泡。高级糖化终产物的自噬降解似乎就是这样。自噬受体p62（Aragon）p62减少了高级糖化终产物的积累，阻断p62选择性自噬导致高级糖化终产物的积累，增加了对糖基化应激的敏感性。不同类型的细胞（包括视网膜、晶状体和成纤维细胞）或不同的组织（如大脑、视网膜、心脏或肝脏）表现出不同的处理糖化应激损伤的能力，建议在未来的干预措施中应考虑细胞和组织依赖性差异。慢性糖化应激或高水平的急性糖化应激会通过糖化这些降解途径的成分并促进蛋白水解损伤而损害蛋白水解途径。在衰老或糖尿病条件下，蛋白质水解途径的缺陷导致糖化蛋白和高级糖化终产物沉积的增加，最终导致高级糖化终产物衍生的组织功能障碍。增强泛素-蛋白酶体系统和自噬可能是限制老年人糖基化蛋白毒性的有效策略。
    文章在《中国神经再生研究（英文版）》杂志2022年 2 月 2 期发表。

https://orcid.org/0000-0001-8390-1581 (Eloy Bejarano)  

Abstract: The worldwide adaptation of a Western lifestyle is associated with the increased consumption of high glycemia diets and an increased prevalence of obesity, metabolic syndrome, and diabetes. These diets increase the risk for a plethora of age-related diseases including cerebrovascular, cardiovascular, and eye-related disorders, which all share a common pathogenic factor: the accumulation of advanced glycation end-products (AGEs) (Semba et al., 2010; Aragno and Mastrocola, 2017). AGEs are a diverse group of pathogenic compounds formed via a non-enzymatic process called glycation in which dietary sugars, or reactive dicarbonyls formed during carbohydrate metabolism, are covalently attached to different biomolecules, inactivating them (Rabbani and Thornalley, 2015). A growing literature indicates that AGEs impact brain function and contribute to initiate and accelerate neurodegeneration and also interfere with the process of neuroregeneration (Li et al., 2012; Vicente Miranda et al., 2017; Fleitas et al., 2018; Bao et al., 2020). In order to avoid AGEs-derived toxicity, our cells have different anti-AGEs defense mechanisms including the clearance of these detrimental compounds through different proteolytic pathways. To date, the lysosomal system (autophagy) and the ubiquitin-proteasome system (UPS) have been identified as proteolytic routes able to degrade AGEs. Unfortunately, the proteolytic capacity declines with age, making tissues more vulnerable to AGEs-derived damage (Uchiki et al., 2012; Rowan et al., 2017; Aragonès et al., 2020). AGEs-modification also compromises the proteolytic machinery, leading to double jeopardy due to the higher glycemia diets or diabetes. Boosting proteolytic pathways might represent a therapeutic strategy to counteract the deposition of toxic, glycated, proteinaceous aggregates in the brain and other tissues with limited regeneration capacity, those most vulnerable to glycation-derived damage.