The Sherpa hypothesis: Phenotype-Protecting Disordered Proteins stabilize the phenotypes of neurons and oligodendrocytes

Abstract

Intrinsically disordered proteins (IDPs) are central to many physiological functions and to various pathologies that include neurodegeneration. They can interact with numerous partner proteins. Here, we introduce the Sherpa hypothesis, according to which a subset of stable IDPs, which 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.