Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.
Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología Universidad Nacional Autónoma de México, Cuernavaca, Morelos, México.
Arch Med Res. 2021 Jan;52(1):1-14. doi: 10.1016/j.arcmed.2020.09.007. Epub 2020 Sep 19.
The ubiquitin-proteasome system is the major pathway for the maintenance of protein homeostasis. Its inhibition causes accumulation of ubiquitinated proteins; this accumulation has been associated with several of the most common neurodegenerative diseases. Several genetic factors have been identified for most neurodegenerative diseases, however, most cases are considered idiopathic, thus making the study of the mechanisms of protein accumulation a relevant field of research. It is often mentioned that the biggest risk factor for neurodegenerative diseases is aging, and several groups have reported an age-related alteration of the expression of some of the 26S proteasome subunits and a reduction of its activity. Proteasome subunits interact with proteins that are known to accumulate in neurodegenerative diseases such as α-synuclein in Parkinson's, tau in Alzheimer's, and huntingtin in Huntington's diseases. These interactions have been explored for several years, but only until recently, we are beginning to understand them. In this review, we discuss the known interactions, the underlying patterns, and the phenotypes associated with the 26S proteasome subunits in the etiology and progression of neurodegenerative diseases where there is evidence of proteasome involvement. Special emphasis is made in reviewing proteasome subunits that interact with proteins known to have an age-related altered expression or to be involved in neurodegenerative diseases to explore key effectors that may trigger or augment their progression. Interestingly, while the causes of age-related reduction of some of the proteasome subunits are not known, there are specific relationships between the observed neurodegenerative disease and the affected proteasome subunits.
泛素-蛋白酶体系统是维持蛋白质内稳态的主要途径。其抑制会导致泛素化蛋白的积累；这种积累与几种最常见的神经退行性疾病有关。大多数神经退行性疾病都已经确定了一些遗传因素，但大多数病例被认为是特发性的，因此研究蛋白质积累的机制是一个相关的研究领域。人们常说神经退行性疾病的最大风险因素是衰老，有几个研究小组已经报告了一些 26S 蛋白酶体亚基的表达随年龄的变化，以及其活性的降低。蛋白酶体亚基与已知在神经退行性疾病中积累的蛋白质相互作用，如帕金森病中的α-突触核蛋白、阿尔茨海默病中的 tau 蛋白和亨廷顿病中的 huntingtin 蛋白。这些相互作用已经被探索了多年，但直到最近，我们才开始理解它们。在这篇综述中，我们讨论了已知的相互作用、潜在的模式以及与神经退行性疾病病因和进展相关的 26S 蛋白酶体亚基的表型，这些疾病有证据表明与蛋白酶体有关。特别强调了与已知具有年龄相关改变表达或与神经退行性疾病有关的蛋白质相互作用的蛋白酶体亚基，以探索可能触发或加剧其进展的关键效应因子。有趣的是，虽然一些蛋白酶体亚基随年龄减少的原因尚不清楚，但观察到的神经退行性疾病与受影响的蛋白酶体亚基之间存在特定的关系。
