Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins

Nat Chem Biol. 2010 Dec;6(12):900-6. doi: 10.1038/nchembio.467. Epub 2010 Oct 31.

Abstract

A hallmark of many neurodegenerative diseases is accumulation of misfolded proteins within neurons, leading to cellular dysfunction and cell death. Although several mechanisms have been proposed to link protein misfolding to cellular toxicity, the connection remains enigmatic. Here, we report a cell death pathway involving protein disulfide isomerase (PDI), a protein chaperone that catalyzes isomerization, reduction and oxidation of disulfides. Through a small molecule screening approach, we discovered five structurally distinct compounds that prevent apoptosis induced by mutant huntingtin protein. Using modified Huisgen cycloaddition chemistry, we then identified PDI as the molecular target of these small molecules. Expression of polyglutamine-expanded huntingtin exon 1 in PC12 cells caused PDI to accumulate at mitochondrial-associated ER membranes and trigger apoptotic cell death via mitochondrial outer-membrane permeabilization. Inhibiting PDI in rat brain cells suppressed the toxicity of mutant huntingtin exon 1 and Aβ peptides processed from the amyloid precursor protein. This pro-apoptotic function of PDI represents a new mechanism linking protein misfolding and apoptotic cell death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Affinity Labels
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Apoptosis / drug effects*
  • Brain / pathology
  • Disulfides / metabolism
  • Endoplasmic Reticulum / enzymology
  • Endoplasmic Reticulum / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Exons / genetics
  • Humans
  • Huntingtin Protein
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Molecular Chaperones / physiology
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • PC12 Cells
  • Protein Disulfide-Isomerases / antagonists & inhibitors*
  • Protein Folding
  • Proteostasis Deficiencies / pathology*
  • Rats
  • Signal Transduction / physiology
  • Small Molecule Libraries

Substances

  • Affinity Labels
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Disulfides
  • Enzyme Inhibitors
  • HTT protein, human
  • Huntingtin Protein
  • Molecular Chaperones
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Small Molecule Libraries
  • Protein Disulfide-Isomerases

Associated data

  • PubChem-Substance/99376484
  • PubChem-Substance/99376485
  • PubChem-Substance/99376486
  • PubChem-Substance/99376487
  • PubChem-Substance/99376488
  • PubChem-Substance/99376489
  • PubChem-Substance/99376490
  • PubChem-Substance/99376491
  • PubChem-Substance/99376492
  • PubChem-Substance/99376493
  • PubChem-Substance/99376494