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


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 A? peptides processed from the amyloid precursor protein. This pro-apoptotic function of PDI represents a new mechanism linking protein misfolding and apoptotic cell death.

SUBMITTER: Hoffstrom BG 

PROVIDER: S-EPMC3018711 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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

Hoffstrom Benjamin G BG   Kaplan Anna A   Letso Reka R   Schmid Ralf S RS   Turmel Gregory J GJ   Lo Donald C DC   Stockwell Brent R BR  

Nature chemical biology 20101031 12


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 dis  ...[more]

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