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

Vic Norris; Judit Oláh; Sergey N Krylov; Vladimir N Uversky; Judit Ovádi

doi:10.1038/s41540-023-00291-8

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

NPJ Syst Biol Appl. 2023 Jul 11;9(1):31. doi: 10.1038/s41540-023-00291-8.

Authors

Vic Norris¹, Judit Oláh², Sergey N Krylov³, Vladimir N Uversky⁴, Judit Ovádi²

Affiliations

¹ Laboratory of Microbiology Signals and Microenvironment, University of Rouen, 76821, Mont Saint Aignan, France. victor.norris@univ-rouen.fr.
² Institute of Enzymology, Research Centre for Natural Sciences, Budapest, H-1117, Hungary.
³ Centre for Research on Biomolecular Interactions, York University, Toronto, ON M3J1P3, Canada.
⁴ Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Neurons*
Oligodendroglia*
Phenotype

Substances

cypermethrin