A comparison of the biochemical modifications caused by toxic and non-toxic protein oligomers in cells

J Cell Mol Med. 2011 Oct;15(10):2106-16. doi: 10.1111/j.1582-4934.2010.01239.x.

Abstract

Peptides and proteins can convert from their soluble forms into highly ordered fibrillar aggregates, giving rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. It is increasingly recognized that protein oligomers forming early in the process of fibril aggregation represent the pathogenic species in protein deposition diseases. The N-terminal domain of the HypF protein from Escherichia coli (HypF-N) has previously been shown to form, under distinct conditions, two types of HypF-N oligomers with indistinguishable morphologies but distinct structural features at the molecular level. Only the oligomer type exposing hydrophobic surfaces and possessing sufficient structural plasticity is toxic (type A), whereas the other type is benign to cultured cells (type B). Here we show that only type A oligomers are able to induce a Ca(2+) influx from the cell medium to the cytosol, to penetrate the plasma membrane, to increase intracellular reactive oxygen species production, lipid peroxidation and release of intracellular calcein, resulting in the activation of the apoptotic pathway. Remarkably, these oligomers can also induce a loss of cholinergic neurons when injected into rat brains. By contrast, markers of cellular stress and viability were unaffected in cultured and rat neuronal cells exposed to type B oligomers. The analysis of the time scales of such effects indicates that the difference of toxicity between the two oligomer types involve the early events of the toxicity cascade, shedding new light on the mechanism of action of protein oligomers and on the molecular targets for the therapeutic intervention against protein deposition diseases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloidogenic Proteins / chemistry
  • Amyloidogenic Proteins / metabolism
  • Animals
  • Apoptosis / drug effects
  • Calcium / metabolism*
  • Carboxyl and Carbamoyl Transferases / chemistry*
  • Carboxyl and Carbamoyl Transferases / pharmacology*
  • Cell Membrane Permeability / drug effects
  • Cells, Cultured
  • Cholinergic Neurons / chemistry
  • Cholinergic Neurons / metabolism*
  • Disease Models, Animal
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / pharmacology*
  • Humans
  • Lipid Peroxidation / drug effects
  • Molecular Targeted Therapy
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism

Substances

  • Amyloidogenic Proteins
  • Escherichia coli Proteins
  • Peptides
  • Reactive Oxygen Species
  • Carboxyl and Carbamoyl Transferases
  • hypF protein, E coli
  • Calcium