Chandran Aswathy, Oliver Haley Jane, Rochet Jean-Christophe
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47907, USA.
Biology (Basel). 2023 Aug 25;12(9):1169. doi: 10.3390/biology12091169.
A hallmark of aging and neurodegenerative diseases is a disruption of proteome homeostasis ("proteostasis") that is caused to a considerable extent by a decrease in the efficiency of protein degradation systems. The ubiquitin proteasome system (UPS) is the major cellular pathway involved in the clearance of small, short-lived proteins, including amyloidogenic proteins that form aggregates in neurodegenerative diseases. Age-dependent decreases in proteasome subunit expression coupled with the inhibition of proteasome function by aggregated UPS substrates result in a feedforward loop that accelerates disease progression. Nuclear factor erythroid 2- like 1 (NFE2L1) is a transcription factor primarily responsible for the proteasome inhibitor-induced "bounce-back effect" regulating the expression of proteasome subunits. NFE2L1 is localized to the endoplasmic reticulum (ER), where it is rapidly degraded under basal conditions by the ER-associated degradation (ERAD) pathway. Under conditions leading to proteasome impairment, NFE2L1 is cleaved and transported to the nucleus, where it binds to antioxidant response elements (AREs) in the promoter region of proteasome subunit genes, thereby stimulating their transcription. In this review, we summarize the role of UPS impairment in aging and neurodegenerative disease etiology and consider the potential benefit of enhancing NFE2L1 function as a strategy to upregulate proteasome function and alleviate pathology in neurodegenerative diseases.
衰老和神经退行性疾病的一个标志是蛋白质组稳态（“蛋白稳态”）的破坏，这在很大程度上是由蛋白质降解系统效率降低所致。泛素蛋白酶体系统（UPS）是参与清除小分子、短寿命蛋白质的主要细胞途径，这些蛋白质包括在神经退行性疾病中形成聚集体的淀粉样蛋白。蛋白酶体亚基表达随年龄增长而降低，再加上聚集的UPS底物对蛋白酶体功能的抑制，导致一个前馈循环，加速疾病进展。核因子红细胞2样1（NFE2L1）是一种转录因子，主要负责蛋白酶体抑制剂诱导的“反弹效应”，调节蛋白酶体亚基的表达。NFE2L1定位于内质网（ER），在基础条件下它通过内质网相关降解（ERAD）途径在内质网中快速降解。在导致蛋白酶体受损的条件下，NFE2L1被切割并转运到细胞核，在细胞核中它与蛋白酶体亚基基因启动子区域的抗氧化反应元件（AREs）结合，从而刺激它们的转录。在这篇综述中，我们总结了UPS损伤在衰老和神经退行性疾病病因学中的作用，并考虑增强NFE2L1功能作为上调蛋白酶体功能和减轻神经退行性疾病病理的一种策略的潜在益处。
