title: 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 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.
authors.affiliation: Howard Hughes Medical Institute, Department of Biological Sciences, Columbia University, New York, New York, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Hoffstrom
authors.forename: Anna
authors.initials: A
authors.lastname: Kaplan
authors.forename: Reka
authors.initials: R
authors.lastname: Letso
authors.forename: Ralf S
authors.initials: RS
authors.lastname: Schmid
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Turmel
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stockwell
mesh_terms: D000345:Affinity Labels; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000473:pathology; D004220:Disulfides / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005091:Exons / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology; D018832:Molecular Chaperones / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D016716:PC12 Cells; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors*; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000473:pathology*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D054852:Small Molecule Libraries
chemical_list: D000345:Affinity Labels; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004220:Disulfides; D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; D019704:Protein Disulfide-Isomerases