PDF(Pubmed)
Abstract：
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.
摘要：
衰老和神经退行性疾病的标志是蛋白质组稳态（“蛋白质稳态”）的破坏，这在很大程度上是由蛋白质降解系统效率的降低引起的。泛素蛋白酶体系统(UPS)是参与小细胞清除的主要细胞通路,短寿命蛋白质，包括在神经退行性疾病中形成聚集体的淀粉样蛋白。蛋白酶体亚基表达的年龄依赖性减少与聚集的UPS底物对蛋白酶体功能的抑制相结合，导致前馈回路加速疾病进展。核因子类红细胞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位于内质网（ER），在基础条件下通过ER相关降解（ERAD）途径快速降解。在导致蛋白酶体受损的条件下，NFE2L1被切割并转运到细胞核，它与蛋白酶体亚基基因启动子区的抗氧化反应元件（AREs）结合，从而刺激它们的转录。在这次审查中,我们总结了UPS损伤在衰老和神经退行性疾病病因中的作用,并考虑了增强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潜在益处.
