A Self-Assembled α-Synuclein Nanoscavenger for Parkinson's Disease
A Self-Assembled α-Synuclein Nanoscavenger for Parkinson's Disease
复制标题
用于帕金森病的自组装α-突触核蛋白纳米清除剂
DOI：
10.1021/acsnano.9b06453
复制
发表时间：
2020-02-01
期刊：
影响因子：
17.1
通讯作者：
Liu, Gang
中科院分区：
文献类型：
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作者：
Liu, Jingyi;Liu, Chao;Liu, Gang
尽管越来越多的证据表明帕金森病（PD）的发病机制与α -突触核蛋白（α -syn）在中脑的聚集密切相关，但α -syn的清除仍然是一个未满足的临床需求。在这里，我们开发了一种简单而有效的策略，通过再沉淀自组装工艺来制造α -同步PD纳米清除剂。基于姜黄素类似物的nanoscavenger （NanoCA）具有控释特性，可刺激主要自噬调节因子转录因子EB （TFEB）的核易位，触发自噬和钙依赖性外泌体分泌，以清除α -syn。预处理NanoCA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，我们设计了一种快速唤醒鼻内给药系统（RA-IDDS），并应用于脑靶向递送纳米oca，该系统对MPTP PD小鼠模型的行为缺陷提供了强大的神经保护，并促进了中脑α -syn单体、低聚物和聚集体的清除。我们的研究结果提供了一种临床可翻译的治疗策略，旨在PD的神经保护和疾病改变。
Although emerging evidence suggests that the pathogenesis of Parkinson's disease (PD) is closely related to the aggregation of alpha-synuclein (alpha-syn) in the midbrain, the clearance of alpha-syn remains an unmet clinical need. Here, we develop a simple and efficient strategy for fabricating the alpha-syn nanoscavenger for PD via 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 alpha-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 alpha-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.