Aptamers are artificial oligonucleotides binding to specific molecular targets. They have a promising role in therapeutics and diagnostics but are often difficult to design. Here, we exploited the catRAPID algorithm to generate aptamers targeting TAR DNA-binding protein 43 (TDP-43), whose aggregation is associated with Amyotrophic Lateral Sclerosis. On the pathway to forming insoluble inclusions, TDP-43 adopts a heterogeneous population of assemblies, many smaller than the diffraction-limit of light. We demonstrated that our aptamers bind TDP-43 and used the tightest interactor, Apt-1, as a probe to visualize TDP-43 condensates with super-resolution microscopy. At a resolution of 10 nanometers, we tracked TDP-43 oligomers undetectable by standard approaches. In cells, Apt-1 interacts with both diffuse and condensed forms of TDP-43, indicating that Apt-1 can be exploited to follow TDP-43 phase transition. The de novo generation of aptamers and their use for microscopy opens a new page to study protein condensation.

适体是与特定分子靶标结合的人工寡核苷酸。它们在治疗和诊断方面具有广阔的前景，但通常难以设计。在这里，我们利用cat RAPID 算法生成针对 TAR DNA 结合蛋白 43 (TDP-43) 的适体，该蛋白的聚集与肌萎缩侧索硬化症相关。在形成不溶性夹杂物的过程中，TDP-43 采用了异质的组装体群体，其中许多小于光的衍射极限。我们证明了我们的适体结合了 TDP-43，并使用最紧密的相互作用子 Apt-1 作为探针，通过超分辨率显微镜观察 TDP-43 凝聚物。我们以 10 纳米的分辨率追踪了标准方法无法检测到的 TDP-43 寡聚物。在细胞中，Apt-1 与弥散形式和浓缩形式的 TDP-43 相互作用，表明 Apt-1 可用于跟踪 TDP-43 相变。适体的从头生成及其在显微镜中的应用为研究蛋白质凝聚开辟了新的一页。