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.

TFE3 和 TFEB 作为溶酶体生物发生和自噬的主要调节因子，可以增强突触蛋白 α-突触核蛋白的降解，从而预防帕金森病 (PD)，并且它们的水平在 PD 患者的大脑中显着降低。然而，TFE3 和 TFEB 在 PD 发病机制中如何受到调节仍然很模糊。在此，我们发现程序性细胞死亡 4 (PDCD4) 促进病理性 α-突触核蛋白积累，通过抑制 TFE3 和 TFEB 翻译来促进 PD 的发展。相反，PDCD4 缺陷显着增加了整体和核 TFE3 和 TFEB 分布，从而减轻了纹状体中 α-突触核蛋白过度表达的 PD 小鼠模型的神经退行性变。从机制上讲，与我们之前报道的 TFEB 一样，PDCD4 也抑制 TFE3 翻译，而不是影响其转录和蛋白质稳定性，从而抑制其核易位和溶酶体功能，最终导致 α-突触核蛋白聚集。我们证明PDCD4的两个MA3结构域通过以eIF-4A依赖性方式结合到mRNA的5'-UTR来介导TFE3的翻译抑制。基于此，我们开发了一种针对pdcd4的穿透血脑屏障的RVG多肽修饰的小RNA药物，通过腹腔注射有效预防α-突触核蛋白神经变性，改善PD症状。总之，我们建议 PDCD4 作为一种 PD 风险蛋白，通过抑制 TFE3 和 TFEB 翻译来促进 α-突触核蛋白神经变性，并进一步提供一种潜在的针对pdcd4 的小 RNA 药物，通过腹腔注射治疗 PD。