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PDCD4 triggers α-synuclein accumulation and motor deficits via co-suppressing TFE3 and TFEB translation in a model of Parkinson's disease.
Cao, Baihui; Chen, Xiaotong; Li, Yubin; Zhou, Tian; Chen, Nuo; Guo, Yaxin; Zhao, Ming; Guo, Chun; Shi, Yongyu; Wang, Qun; Du, Xuexiang; Zhang, Lining; Li, Yan.
Afiliación
  • Cao B; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Chen X; Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
  • Li Y; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Zhou T; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Chen N; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Guo Y; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Zhao M; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Guo C; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Shi Y; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Wang Q; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Du X; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Zhang L; Department of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China. zhanglining@sdu.edu.cn.
  • Li Y; Department of Pathogen Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China. liyan2015@sdu.edu.cn.
NPJ Parkinsons Dis ; 10(1): 146, 2024 Aug 06.
Article en En | MEDLINE | ID: mdl-39107320
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.

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: NPJ Parkinsons Dis Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: NPJ Parkinsons Dis Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos