Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138667, Singapore.
Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
Biomolecules. 2022 Mar 27;12(4):507. doi: 10.3390/biom12040507.
α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise α-syn domains interfere with α-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the α-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of α-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective α-syn targeted therapy is still plagued by low permeability across the blood-brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain.
α-突触核蛋白（α-syn）是一种突触前、与脂结合的蛋白，与帕金森病（PD）、路易体痴呆（DLB）和阿尔茨海默病（AD）中的神经病理学密切相关。在正常生理学中，α-syn 在促进内吞作用和胞吐作用方面发挥着关键作用。有趣的是，α-syn 精确结构域的突变和修饰会干扰 α-syn 的寡聚化和成核，从而对突触前囊泡动力学、蛋白质表达和线粒体特征产生负面影响。此外，α-syn 寡聚物整合到突触前膜会导致孔形成、离子内流和兴奋性毒性。针对 α-syn 特定结构域的靶向治疗方法，包括使用小分子有机化合物、单克隆抗体和合成肽，正在进行筛选和开发。然而，有效的 α-syn 靶向治疗的前景仍然受到血脑屏障（BBB）通透性低和进入突触前轴突末梢能力差的困扰。本综述提出了对现有策略的修改，包括使用新型封装技术，如脂质纳米颗粒，绕过 BBB 将这些药物递送到大脑中。
