School of Medicine , Xiamen University , Xiamen 361102 , China.
State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen 361102 , China.
ACS Nano. 2020 Feb 25;14(2):1533-1549. doi: 10.1021/acsnano.9b06453. Epub 2020 Feb 10.
Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (α-syn) in the midbrain, the clearance of α-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the α-syn nanoscavenger for PD a reprecipitation self-assembly procedure. The curcumin analogue-based nanoscavenger (NanoCA) is engineered to be capable of a controlled-release property to stimulate nuclear translocation of the major autophagy regulator, transcription factor EB (TFEB), triggering both autophagy and calcium-dependent exosome secretion for the clearance of α-syn. Pretreatment of NanoCA protects cell lines and primary neurons from MPP-induced neurotoxicity. More importantly, a rapid arousal intranasal delivery system (RA-IDDS) was designed and applied for the brain-targeted delivery of NanoCA, which affords robust neuroprotection against behavioral deficits and promotes clearance of monomer, oligomer, and aggregates of α-syn in the midbrain of an MPTP mouse model of PD. Our findings provide a clinically translatable therapeutic strategy aimed at neuroprotection and disease modification in PD.
虽然新出现的证据表明帕金森病 (PD) 的发病机制与中脑 α-突触核蛋白 (α-syn) 的聚集密切相关，但 α-syn 的清除仍然是未满足的临床需求。在这里，我们开发了一种制造用于 PD 的 α-syn 纳米清除剂的简单高效策略 - 重沉淀自组装程序。基于姜黄素类似物的纳米清除剂（NanoCA）被设计为能够控制释放特性，以刺激主要自噬调节剂转录因子 EB (TFEB) 的核易位，引发自噬和钙依赖性外体分泌以清除 α-syn。NanoCA 的预处理可保护细胞系和原代神经元免受 MPP 诱导的神经毒性。更重要的是，设计并应用了一种快速唤醒鼻腔给药系统（RA-IDDS）用于 NanoCA 的脑靶向递送，该系统可提供针对 PD 中 MPTP 小鼠模型中行为缺陷的强大神经保护作用，并促进中脑 α-syn 单体、寡聚体和聚集体的清除。我们的研究结果提供了一种具有临床转化潜力的治疗策略，旨在针对 PD 进行神经保护和疾病修饰。
