The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins
Open accessAbstract
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 exon1 and Aβ peptides processed from the amyloid precursor protein. This pro-apoptotic function of PDI provides a new mechanism linking protein misfolding and apoptotic cell death.
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1 retracted
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Self-citationProteome-wide covalent ligand discovery in native biological systems
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Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases
Hetz, C., & Mollereau, B. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3689 · Cited by 684
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BCL-2 family: integrating stress responses at the ER to control cell demise
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Metadata
- Authors
- Hoffstrom, B. G., Kaplan, A., Letso, R., Schmid, R. S., Turmel, G. J., Lo, D. C., & Stockwell, B. R.
- Venue
- Nature Chemical Biology
- Published
- 2010-10-31
- Volume
- 6
- Issue
- 12
- Pages
- 900-906
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2015902113
- Cited by
- 310
- References
- 50
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- green
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- Hoffstrom, B. G., Kaplan, A., Letso, R., Schmid, R. S., Turmel, G. J., Lo, D. C., & Stockwell, B. R. (2010). Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins. Nature Chemical Biology. https://doi.org/10.1038/nchembio.467
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