α-Synuclein (α-syn) overload is strongly associated with Parkinson disease (PD), and reduction of the α-syn level by targeting the peptide-based system through the autophagy-lysosomal pathway (ALP) is a promising strategy to delay PD progression. However, if the ALP is comprised, targeting the peptide-based proteasomal degradation system would be a good alternative. In this study, we designed a fusion peptide containing an α-syn-binding domain and a short strong proteasome-targeting motif. Our results reveal that this peptide could specifically bind to α-syn, and direct it to the proteasomes for degradation in a recombinant expression system. Furthermore, by adding a membrane-penetrating motif to this fusion peptide, we demonstrated that it could penetrate into cells and consequently suppress the cellular α-syn level through proteasome degradation in a dose- and time-dependent manner. Functionally, these effects rescued the mitochondrial dysfunction and cellular defects caused by α-syn overexpression in the cultured cells and primary neurons.

α-突触核蛋白（α-syn）过载与帕金森病（PD）密切相关，通过自噬溶酶体途径（ALP）靶向基于肽的系统来降低α-syn水平是延缓PD的一种有前途的策略进展。但是，如果包含ALP，靶向基于肽的蛋白酶体降解系统将是一个很好的选择。在这项研究中，我们设计了一个融合肽，其中包含一个α-syn结合结构域和一个短而强的蛋白酶体靶向基序。我们的结果表明，该肽可以特异性结合α-syn，并将其引导至蛋白酶体以在重组表达系统中降解。此外，通过在该融合肽上添加穿透膜的基序，我们证明了它可以渗透到细胞中，从而通过蛋白酶体降解以剂量和时间依赖性的方式抑制细胞的α-syn水平。在功能上，这些作用挽救了由α-syn在培养细胞和原代神经元中过度表达引起的线粒体功能障碍和细胞缺陷。