EPB41L4A-AS1 是维持基础自噬以调节 Aβ 清除的必要条件

IF 5.4 Q1 GERIATRICS & GERONTOLOGY NPJ Aging and Mechanisms of Disease Pub Date : 2024-05-04 DOI:10.1038/s41514-024-00152-6
Ziqiang Wang, Ruomei Wang, Lixin Niu, Xiaoyan Zhou, Jinxiang Han, Kun Li
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引用次数: 0

摘要

阿尔茨海默病(AD)是最常见的神经退行性疾病,以β淀粉样蛋白(Aβ)斑块沉积为特征。Aβ 由 β 和 γ 分泌酶裂解淀粉样前体蛋白生成,并由神经胶质细胞介导的自噬作用清除。细胞内 Aβ 生成和清除的失衡是导致注意力缺失症发病的致病因素。然而,其确切的分子机制仍不清楚。我们之前的研究发现,EPB41L4A-AS1是一种与衰老相关的长非编码RNA(lncRNA),它在AD患者中被抑制。在这项研究中,我们发现下调 EPB41L4A-AS1 会通过降低多个自噬相关基因的表达水平来抑制神经胶质细胞介导的 Aβ 清除。我们发现,EPB41L4A-AS1调控重要的组蛋白乙酰转移酶--氨基酸合成总控制5样2的表达,从而影响自噬相关基因转录起始位点附近的组蛋白乙酰化、巴豆酰化和乳酰化,最终影响其转录。总之,本研究揭示了EPB41L4A-AS1通过介导Aβ清除而成为一种与AD相关的lncRNA,并深入揭示了EPB41L4A-AS1在基因表达和AD发病机制中的表观遗传调控机制。
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EPB41L4A-AS1 is required to maintain basal autophagy to modulates Aβ clearance

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques. Aβ is generated from the cleavage of the amyloid precursor protein by β and γ-secretases and cleared by neuroglial cells mediated autophagy. The imbalance of the intracellular Aβ generation and clearance is the causative factor for AD pathogenesis. However, the exact underlying molecular mechanisms remain unclear. Our previous study reported that EPB41L4A-AS1 is an aging-related long non-coding RNA (lncRNA) that is repressed in patients with AD. In this study, we found that downregulated EPB41L4A-AS1 in AD inhibited neuroglial cells mediated-Aβ clearance by decreasing the expression levels of multiple autophagy-related genes. We found that EPB41L4A-AS1 regulates the expression of general control of amino acid synthesis 5-like 2, an important histone acetyltransferase, thus affecting histone acetylation, crotonylation, and lactylation near the transcription start site of autophagy-related genes, ultimately influencing their transcription. Collectively, this study reveals EPB41L4A-AS1 as an AD-related lncRNA via mediating Aβ clearance and provides insights into the epigenetic regulatory mechanism of EPB41L4A-AS1 in gene expression and AD pathogenesis.

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来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
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8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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