NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome.

IF 3.5 3区医学 Q2 NEUROSCIENCES

Frontiers in Molecular Neuroscience Pub Date : 2025-05-01 eCollection Date: 2025-01-01 DOI:10.3389/fnmol.2025.1551571

Hossein Khodadadi, Kamila Łuczyńska, Dawid Winiarczyk, Paweł Leszczyński, Hiroaki Taniguchi

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引用次数: 0

Abstract

Maintaining proteostasis is critical for neuronal health, with its disruption underpinning the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Nuclear Factor Erythroid 2-Related Factor 1 (NFE2L1) has emerged as a key regulator of proteostasis, integrating proteasome function, autophagy, and ferroptosis to counteract oxidative stress and protein misfolding. This review synthesizes current knowledge on the role of NFE2L1 in maintaining neuronal homeostasis, focusing on its mechanisms for mitigating proteotoxic stress and supporting cellular health, offering protection against neurodegeneration. Furthermore, we discuss the pathological implications of NFE2L1 dysfunction and explore its potential as a therapeutic target. By highlighting gaps in the current understanding and presenting future research directions, this review aims to elucidate NFE2L1's role in advancing treatment strategies for neurodegenerative diseases.

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NFE2L1作为神经退行性疾病中蛋白平衡的中枢调节因子：与自噬、铁凋亡和蛋白酶体的相互作用

维持蛋白质平衡对神经元健康至关重要，它的破坏是神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿病）进展的基础。核因子-红系2相关因子1 （NFE2L1）作为蛋白质稳态的关键调节因子，整合蛋白酶体功能、自噬和铁凋亡来对抗氧化应激和蛋白质错误折叠。本综述综合了目前关于NFE2L1在维持神经元稳态中的作用的知识，重点介绍了其减轻蛋白毒性应激和支持细胞健康的机制，并提供了防止神经变性的保护。此外，我们讨论了NFE2L1功能障碍的病理意义，并探讨了其作为治疗靶点的潜力。通过强调目前认识的差距和未来的研究方向，本综述旨在阐明NFE2L1在推进神经退行性疾病治疗策略中的作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Molecular Neuroscience NEUROSCIENCES-

CiteScore

5.70

自引率

2.10%

发文量

669

审稿时长

14 weeks

期刊介绍： Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.