Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins.

Published

Journal Article

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.

Full Text

Cited Authors

  • Hoffstrom, BG; Kaplan, A; Letso, R; Schmid, RS; Turmel, GJ; Lo, DC; Stockwell, BR

Published Date

  • December 2010

Published In

Volume / Issue

  • 6 / 12

Start / End Page

  • 900 - 906

PubMed ID

  • 21079601

Pubmed Central ID

  • 21079601

Electronic International Standard Serial Number (EISSN)

  • 1552-4469

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.467

Language

  • eng