PDCD4 triggers α-synuclein accumulation and motor deficits via co-suppressing TFE3 and TFEB translation in a model of Parkinson's disease.

IF 6.7 1区 医学 Q1 NEUROSCIENCES NPJ Parkinson's Disease Pub Date : 2024-08-06 DOI:10.1038/s41531-024-00760-9
Baihui Cao, Xiaotong Chen, Yubin Li, Tian Zhou, Nuo Chen, Yaxin Guo, Ming Zhao, Chun Guo, Yongyu Shi, Qun Wang, Xuexiang Du, Lining Zhang, Yan Li
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Abstract

TFE3 and TFEB, as the master regulators of lysosome biogenesis and autophagy, are well characterized to enhance the synaptic protein α-synuclein degradation in protecting against Parkinson's disease (PD) and their levels are significantly decreased in the brain of PD patients. However, how TFE3 and TFEB are regulated during PD pathogenesis remains largely vague. Herein, we identified that programmed cell death 4 (PDCD4) promoted pathologic α-synuclein accumulation to facilitate PD development via suppressing both TFE3 and TFEB translation. Conversely, PDCD4 deficiency significantly augmented global and nuclear TFE3 and TFEB distributions to alleviate neurodegeneration in a mouse model of PD with overexpressing α-synuclein in the striatum. Mechanistically, like TFEB as we reported before, PDCD4 also suppressed TFE3 translation, rather than influencing its transcription and protein stability, to restrain its nuclear translocation and lysosomal functions, eventually leading to α-synuclein aggregation. We proved that the two MA3 domains of PDCD4 mediated the translational suppression of TFE3 through binding to its 5'-UTR of mRNA in an eIF-4A dependent manner. Based on this, we developed a blood-brain barrier penetrating RVG polypeptide modified small RNA drug against pdcd4 to efficiently prevent α-synuclein neurodegeneration in improving PD symptoms by intraperitoneal injections. Together, we suggest PDCD4 as a PD-risk protein to facilitate α-synuclein neurodegeneration via suppressing TFE3 and TFEB translation and further provide a potential small RNA drug against pdcd4 to treat PD by intraperitoneal injections.

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在帕金森病模型中,PDCD4通过共同抑制TFE3和TFEB翻译引发α-突触核蛋白积累和运动障碍。
TFE3和TFEB作为溶酶体生物生成和自噬的主调控因子,在保护帕金森病(PD)中可增强突触蛋白α-突触核蛋白的降解,其在帕金森病患者脑中的水平显著下降。然而,在帕金森病发病过程中,TFE3和TFEB是如何被调控的目前仍很模糊。在这里,我们发现程序性细胞死亡4(PDCD4)通过抑制TFE3和TFEB的翻译,促进病理性α-突触核蛋白的积累,从而促进帕金森病的发展。相反,在纹状体中过表达α-突触核蛋白的脊髓灰质炎小鼠模型中,PDCD4的缺乏会显著增加TFE3和TFEB的全局和核分布,从而缓解神经退行性变。从机理上讲,与我们之前报道的TFEB一样,PDCD4也抑制了TFE3的翻译,而不是影响其转录和蛋白稳定性,从而抑制其核转运和溶酶体功能,最终导致α-突触核蛋白聚集。我们证明,PDCD4的两个MA3结构域通过与TFE3 mRNA的5'-UTR结合,以依赖eIF-4A的方式介导了对TFE3的翻译抑制。在此基础上,我们开发了一种可穿透血脑屏障的RVG多肽修饰的针对pdcd4的小RNA药物,通过腹腔注射有效地阻止了α-突触核蛋白神经变性,改善了PD症状。综上所述,我们认为PDCD4是一种PD风险蛋白,可通过抑制TFE3和TFEB翻译促进α-突触核蛋白神经变性,并进一步提供了一种潜在的针对pdcd4的小RNA药物,通过腹腔注射治疗PD。
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
NPJ Parkinson's Disease
NPJ Parkinson's Disease Medicine-Neurology (clinical)
CiteScore
9.80
自引率
5.70%
发文量
156
审稿时长
11 weeks
期刊介绍: npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
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