Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

中文翻译：

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用于突触核蛋白病的基于单域抗体的蛋白质降解剂


突触核蛋白病是一组神经退行性疾病，其特征是 α-突触核蛋白 (α-syn) 在大脑中积聚，导致运动和神经精神症状。目前，突触核蛋白病尚无已知的治疗方法，治疗主要集中在症状管理上。在这项研究中，我们开发了一种基于单域抗体 (sdAb) 的蛋白质降解剂，其特征旨在增强 α-syn 的蛋白酶体降解。这种 sdAb 衍生物同时靶向 α-syn 和 Cereblon (CRBN)（E3-泛素连接酶 CRL4CRBN 的底物受体），从而诱导 α-syn 泛素化和蛋白酶体降解。我们的结果表明，除了内源性溶酶体降解机制之外，该治疗候选药物还增强了 α-syn 的蛋白酶体降解。通过促进 α-syn 的蛋白酶体降解，我们提高了原代培养物和突触核蛋白病小鼠模型中 α-syn 的清除率。这些发现表明我们的基于 sdAb 的蛋白质降解剂是突触核蛋白病的有前途的治疗候选者。考虑到只有一小部分抗体进入大脑，与完整抗体相比，更有效的 sdAb 可以更有效地进入大脑，从而增强基于抗体的疗法的临床益处。