Laboratory of Microbiology Signals and Microenvironment, University of Rouen, 76821, Mont Saint Aignan, France.
Institute of Enzymology, Research Centre for Natural Sciences, Budapest, H-1117, Hungary.
NPJ Syst Biol Appl. 2023 Jul 11;9(1):31. doi: 10.1038/s41540-023-00291-8.
Intrinsically disordered proteins (IDPs), which can interact with many partner proteins, are central to many physiological functions and to various pathologies that include neurodegeneration. Here, we introduce the Sherpa hypothesis, according to which a subset of stable IDPs that we term Phenotype-Preserving Disordered Proteins (PPDP) play a central role in protecting cell phenotypes from perturbations. To illustrate and test this hypothesis, we computer-simulate some salient features of how cells evolve and differentiate in the presence of either a single PPDP or two incompatible PPDPs. We relate this virtual experiment to the pathological interactions between two PPDPs, α-synuclein and Tubulin Polymerization Promoting Protein/p25, in neurodegenerative disorders. Finally, we discuss the implications of the Sherpa hypothesis for aptamer-based therapies of such disorders.
无规则蛋白质（IDPs）可以与许多伴侣蛋白相互作用，它们是许多生理功能的核心，也是包括神经退行性变在内的各种病理学的基础。在这里，我们引入 Sherpa 假说，根据该假说，我们称之为保留表型的无序蛋白质（PPDP）的稳定 IDP 亚类在保护细胞表型免受干扰方面起着核心作用。为了说明和验证这一假说，我们通过计算机模拟了在单个 PPDP 或两种不兼容的 PPDP 存在的情况下细胞如何进化和分化的一些显著特征。我们将这个虚拟实验与神经退行性疾病中两种 PPDP（α-突触核蛋白和微管蛋白聚合促进蛋白/p25）之间的病理性相互作用联系起来。最后，我们讨论了 Sherpa 假说对这些疾病基于适体的治疗的意义。
