Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases

Prajwal Ciryam, Rishika Kundra, Richard I. Morimoto, Christopher M. Dobson, Michele Vendruscolo*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

87 Scopus citations

Abstract

The solubility of proteins is an essential requirement for their function. Nevertheless, these ubiquitous molecules can undergo aberrant aggregation when the protein homeostasis system becomes impaired. Here we ask: what are the driving forces for protein aggregation in the cellular environment? Emerging evidence suggests that this phenomenon arises at least in part because the native states of many proteins are inherently metastable when their cellular concentrations exceed their critical values. Such 'supersaturated' proteins, which form a 'metastable subproteome', are strongly driven towards aggregation, and are over-represented in specific biochemical pathways associated with neurodegenerative conditions. These observations suggest that effective therapeutic approaches designed to combat neurodegenerative diseases could be aimed at enhancing the ability of the cell to maintain the homeostasis of the metastable subproteome.

Original languageEnglish (US)
Pages (from-to)72-77
Number of pages6
JournalTrends in Pharmacological Sciences
Volume36
Issue number2
DOIs
StatePublished - Feb 2015

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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