Shen Linjing, Zhang Jianchao, Wang Zhaoran, Liu Yaxuan, Cui Shengjin, Rao Hai
Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
Clinical Laboratory, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
J Biol Chem. 2025 Jul 2;301(8):110449. doi: 10.1016/j.jbc.2025.110449.
Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is associated with α-synuclein (α-syn) overexpression or mutation, leading to harmful aggregates and neuronal apoptosis. Effective drugs that inhibit or reduce α-syn accumulation remain challenging. Targeted protein degradation (TPD) technology offers a novel solution by utilizing the ubiquitin-proteasome pathway to target specific proteins for destruction. Here, we have developed Proteolysis Targeting Chimera (PROTAC) to target α-syn for degradation. Specifically, our PROTACs employ the amino acid arginine (Arg) as the E3 ligase ligand and a benzothiazole-aniline variant as the warhead for α-syn. The efficacy of these PROTACs in degrading α-syn and its aggregates was tested in mammalian cells and Caenorhabditis elegans (C. elegans) models. Arg-PEG1-T shows the highest degradation effect in mammalian cells for both wild-type α-syn and the α-syn (A53T) mutant. UBR1 is the ubiquitin E3 ligase responsible for PROTAC-mediated degradation. Furthermore, Arg-PEG1-T significantly reduces α-syn aggregates and associated toxicities in both mammalian cells and C. elegans. These findings highlight the potential of a single amino acid-based PROTAC targeting α-syn for degradation, representing a possible therapeutic approach for PD and other synucleinopathies.
帕金森病（PD）是第二常见的神经退行性疾病，与α-突触核蛋白（α-syn）的过度表达或突变有关，会导致有害聚集体的形成和神经元凋亡。开发能够抑制或减少α-syn积累的有效药物仍然具有挑战性。靶向蛋白降解（TPD）技术通过利用泛素-蛋白酶体途径靶向特定蛋白质进行降解，提供了一种新的解决方案。在此，我们开发了靶向蛋白水解嵌合体（PROTAC）来靶向降解α-syn。具体而言，我们的PROTACs采用氨基酸精氨酸（Arg）作为E3连接酶配体，并使用苯并噻唑-苯胺变体作为α-syn的弹头。在哺乳动物细胞和秀丽隐杆线虫（C. elegans）模型中测试了这些PROTACs降解α-syn及其聚集体的效果。Arg-PEG1-T对野生型α-syn和α-syn（A53T）突变体在哺乳动物细胞中均表现出最高的降解效果。UBR1是负责PROTAC介导降解的泛素E3连接酶。此外，Arg-PEG1-T在哺乳动物细胞和秀丽隐杆线虫中均显著减少了α-syn聚集体及其相关毒性。这些发现突出了基于单个氨基酸的靶向α-syn降解的PROTAC的潜力，代表了一种针对帕金森病和其他突触核蛋白病的可能治疗方法。
