英国剑桥大学William A. McEwan研究组通过簇激活降解剂选择性去除病理性tau蛋白。相关论文于2024年8月30日发表在《科学》杂志上。

该课题组研究人员将TRIM21的RING结构域定位为目标特异性纳米体，以创建能够选择性降解聚集蛋白的细胞内表达构建体。

研究组针对绿色荧光蛋白标记的组蛋白2B (H2B-GFP)和tau(一种在阿尔茨海默氏症和其他神经退行性疾病中病理聚集的蛋白质)评估了这种方法。RING纳米体降解剂在培养和体内阻止或逆转tau聚集，对单体tau的影响最小。这种方法可能对许多由细胞内蛋白聚集引起的疾病具有治疗潜力。

据介绍，选择性降解病理蛋白聚集体，同时保留单体形式是主要的治疗兴趣。由于TRIM21 RING结构域的簇集对于激活至关重要，因此TRIM21激酶在特定的装配状态下特异性地降解与抗体结合的蛋白质，然而有效地靶向细胞内装配体仍然是一个挑战。

附：英文原文

Title: Aggregate-selective removal of pathological tau by clustering-activated degraders

Author: Jonathan Benn, Shi Cheng, Sophie Keeling, Annabel E. Smith, Marina J. Vaysburd, Dorothea Bken, Lauren V. C. Miller, Taxiarchis Katsinelos, Catarina Franco, Elian Dupré, Clément Danis, Isabelle Landrieu, Luc Buée, David Klenerman, Leo C. James, William A. McEwan

Issue&Volume: 2024-08-30

Abstract: Selective degradation of pathological protein aggregates while sparing monomeric forms is of major therapeutic interest. The E3 ligase tripartite motif–containing protein 21 (TRIM21) degrades antibody-bound proteins in an assembly state–specific manner due to the requirement of TRIM21 RING domain clustering for activation, yet effective targeting of intracellular assemblies remains challenging. Here, we fused the RING domain of TRIM21 to a target-specific nanobody to create intracellularly expressed constructs capable of selectively degrading assembled proteins. We evaluated this approach against green fluorescent protein–tagged histone 2B (H2B-GFP) and tau, a protein that undergoes pathological aggregation in Alzheimer’s and other neurodegenerative diseases. RING-nanobody degraders prevented or reversed tau aggregation in culture and in vivo, with minimal impact on monomeric tau. This approach may have therapeutic potential for the many disorders driven by intracellular protein aggregation.

DOI: adp5186

Source: https://www.science.org/doi/10.1126/science.adp5186