FoxO1 可降低 BV-2 小神经胶质细胞中α-突触核蛋白预成纤维诱导的线粒体 ROS 水平。

IF 4.5 2区 医学 Q2 CELL BIOLOGY Inflammation Pub Date : 2024-08-15 DOI:10.1007/s10753-024-02119-x
Jiyeon Na, Hye Guk Ryu, Haeun Park, Hyeonwoo Park, Eunmin Lee, Younwoo Nam, Hyerynn Kim, Sang-Min Jang, Do-Yeon Kim, Sangjune Kim
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摘要

帕金森病(Parkinson's disease,PD)是一种复杂的神经退行性疾病,其特征是多巴胺能神经元的逐渐退化,尤其是在黑质紧密区(substantia nigra pars compacta,SNc)。转录因子 FoxO1 的失调与包括阿尔茨海默病和帕金森病在内的多种神经退行性疾病有关,但其中涉及的具体机制尚不完全清楚。本研究探讨了α-突触核蛋白预成纤维(PFF)对BV-2小胶质细胞的影响,重点是分子特征的变化及其对神经元变性的影响。我们的研究结果表明,PFF 处理可显著提高 FoxO1 mRNA(p = 0.0443)和蛋白质(p = 0.0216)水平,导致其核转位(p = 0.0142),并增强参与活性氧(ROS)解毒的基因表达,如过氧化氢酶(Cat,p = 0.0249)和超氧化物歧化酶 2(Sod2,p = 0.0313)。此外,我们还观察到 PFF 处理会提高线粒体 ROS 水平。然而,缺乏 FoxO1 或用 FoxO1 抑制剂处理的细胞对 PFF 诱导的 ROS 表现出更大的脆弱性,这归因于 ROS 解毒酶 Cat 和 Sod2 的表达减少(p = 0.0249)。
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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FoxO1 Alleviates the Mitochondrial ROS Levels Induced by α-Synuclein Preformed Fibrils in BV-2 Microglial Cells.

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons, especially in the substantia nigra pars compacta (SNc). Dysregulation of the transcription factor FoxO1 is associated with various neurodegenerative conditions, including Alzheimer's disease and PD, though the specific mechanisms involved are not fully understood. This study explores the effects of α-Synuclein preformed fibrils (PFF) on BV-2 microglial cells, focusing on changes in molecular characteristics and their impact on neuronal degeneration. Our results demonstrate that PFF treatment significantly increases FoxO1 mRNA (p = 0.0443) and protein (p = 0.0216) levels, leading to its nuclear translocation (p = 0.0142) and enhanced expression of genes involved in the detoxification of reactive oxygen species (ROS), such as Catalase (Cat, p = 0.0249) and superoxide dismutase 2 (Sod2, p = 0.0313). Furthermore, we observed that PFF treatment elevates mitochondrial ROS levels. However, cells lacking FoxO1 or treated with FoxO1 inhibitors showed increased vulnerability to PFF-induced ROS, attributed to reduced expression of ROS detoxifying enzymes Cat and Sod2 (p < 0.0001). Besides enhancing ROS production, inhibiting FoxO1 also heightens neurotoxicity induced by PFF treatment in microglia-conditioned medium (p < 0.0001). Conversely, treatment with N-acetylcysteine or bacterial superoxide dismutase A mitigated the ROS increase induced by PFF (p < 0.0001). These findings suggest the essential role of FoxO1 in regulating ROS levels, which helps alleviate pathology in PFF-induced PD models. Our study provides insights into the genetic mechanisms of PD and suggests potential pathways for developing novel therapeutic strategies.

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来源期刊
Inflammation
Inflammation 医学-免疫学
CiteScore
9.70
自引率
0.00%
发文量
168
审稿时长
3.0 months
期刊介绍: Inflammation publishes the latest international advances in experimental and clinical research on the physiology, biochemistry, cell biology, and pharmacology of inflammation. Contributions include full-length scientific reports, short definitive articles, and papers from meetings and symposia proceedings. The journal''s coverage includes acute and chronic inflammation; mediators of inflammation; mechanisms of tissue injury and cytotoxicity; pharmacology of inflammation; and clinical studies of inflammation and its modification.
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