ER chaperone-metal interactions: links to protein folding disorders

Neurotoxicology. 2012 Jun;33(3):545-57. doi: 10.1016/j.neuro.2012.02.007. Epub 2012 Feb 20.


Chaperones in the endoplasmic reticulum play vital roles in the folding, assembly, and post-translational modification of secretory proteins and also recycle, refold, or initiate degradation of misfolded proteins. Chaperone deficiencies in either amount or function are implicated in the etiology or pathogenesis of Alzheimer's disease and other protein folding disorders of the central nervous system. In this review, we discuss evidence that chaperones become pathologic through deleterious interactions with metals and then promote protein folding disorders. The "master regulator" chaperone GRP78 in the endoplasmic reticulum is a compelling subject for investigation in this context because it is located at the hub of signaling pathways in a complex chaperone network. It has therefore been studied by several laboratories in conjunction with exposure to toxic metals. The key points of this review are that metals are implicated in the etiology or pathogenesis of Alzheimer's disease and other protein folding disorders, metals induce the expression GRP78, often associated with oxidative stress, some metals bind to GRP78, and lead (Pb) impairs GRP78 function when it binds to GRP78. If certain metals do indeed cause or promote the aggregation of toxic proteins in the central nervous system, as the available evidence indicates, the identification of the mechanisms by which they act would provide valuable leads for the development of therapies to prevent or reverse toxic protein aggregation.

Publication types

  • Review

MeSH terms

  • Animals
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / pathology
  • Heat-Shock Proteins / metabolism
  • Humans
  • Metals / toxicity*
  • Molecular Chaperones / metabolism*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neurotoxicity Syndromes / etiology*
  • Neurotoxicity Syndromes / metabolism
  • Neurotoxicity Syndromes / pathology
  • Protein Folding
  • Proteostasis Deficiencies / chemically induced*
  • Proteostasis Deficiencies / metabolism
  • Proteostasis Deficiencies / pathology
  • Risk Assessment
  • Risk Factors


  • Heat-Shock Proteins
  • Metals
  • Molecular Chaperones
  • molecular chaperone GRP78