TFE3 介导的神经保护:清除AAV-α-突触核蛋白帕金森病模型中聚集的α-突触核蛋白和积累的线粒体

IF 6.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Genes & Diseases Pub Date : 2024-09-07 DOI:10.1016/j.gendis.2024.101429
Xin He, Mulan Chen, Yepeng Fan, Bin Wu, Zhifang Dong
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引用次数: 0

摘要

帕金森病(Parkinson's disease,PD)是一种神经退行性疾病,其特征是神经元内含有聚集的α-突触核蛋白(α-Syn)的纤维包裹体。虽然帕金森病的病理是多方面的,但α-Syn的聚集和线粒体功能障碍是其发病机制中公认的标志。最近,转录因子 TFE3 成为自噬和代谢过程的调节因子。然而,TFE3是否能促进α-Syn的降解并调节多巴胺能神经元的线粒体代谢仍不清楚。在本研究中,我们证明了在α-Syn过表达的帕金森病模型中,TFE3的过表达能显著缓解多巴胺能神经元的丢失,并减少酪氨酸羟化酶阳性纤维密度的下降,从而恢复运动功能。从机理上讲,TFE3的过表达逆转了α-Syn介导的自噬损伤,导致α-Syn降解增强、聚集减少。此外,TFE3 的过表达抑制了 α-Syn 的传播。TFE3 的过量表达还逆转了 Parkin 的下调,促进了累积线粒体的清除,并恢复了 PGC1-α 和 TFAM 的表达,从而增强了腺相关病毒-α-Syn 模型中线粒体的生物生成。这些研究结果进一步强调了TFE3在帕金森病中的神经保护作用,并深入揭示了其潜在机制,提示TFE3是帕金森病的潜在治疗靶点。
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TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease
Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions containing aggregated α-synuclein (α-Syn). While the pathology of PD is multifaceted, the aggregation of α-Syn and mitochondrial dysfunction are well-established hallmarks in its pathogenesis. Recently, TFE3, a transcription factor, has emerged as a regulator of autophagy and metabolic processes. However, it remains unclear whether TFE3 can facilitate the degradation of α-Syn and regulate mitochondrial metabolism specifically in dopaminergic neurons. In this study, we demonstrate that TFE3 overexpression significantly mitigates the loss of dopaminergic neurons and reduces the decline in tyrosine hydroxylase-positive fiber density, thereby restoring motor function in an α-Syn overexpression model of PD. Mechanistically, TFE3 overexpression reversed α-Syn-mediated impairment of autophagy, leading to enhanced α-Syn degradation and reduced aggregation. Additionally, TFE3 overexpression inhibited α-Syn propagation. TFE3 overexpression also reversed the down-regulation of Parkin, promoting the clearance of accumulated mitochondria, and restored the expression of PGC1-α and TFAM, thereby enhancing mitochondrial biogenesis in the adeno-associated virus-α-Syn model. These findings further underscore the neuroprotective role of TFE3 in PD and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target for PD.
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来源期刊
Genes & Diseases
Genes & Diseases Multiple-
CiteScore
7.30
自引率
0.00%
发文量
347
审稿时长
49 days
期刊介绍: Genes & Diseases is an international journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch. Aims and Scopes Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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