Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-00203-5
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Funding
- National Health and Medical Research Council [APP1049458, APP1049459, APP1102059]
- Australian Research Council [FT120100039, DP170103093, DE170100058]
- La Trobe University
- Melbourne Neuroscience Institute (University of Melbourne)
- University of Melbourne
- Ministry of Education Singapore [R-172-000-297-112]
- Agency for Science, Technology and Research Strategic Positioning Fund for Genetic Orphan Diseases grant [SPF2012/005]
- Australian Research Council [FT120100039] Funding Source: Australian Research Council
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When proteostasis becomes unbalanced, unfolded proteins can accumulate and aggregate. Here we report that the dye, tetraphenylethene maleimide (TPE-MI) can be used to measure cellular unfolded protein load. TPE-MI fluorescence is activated upon labelling free cysteine thiols, normally buried in the core of globular proteins that are exposed upon unfolding. Crucially TPE-MI does not become fluorescent when conjugated to soluble glutathione. We find that TPE-MI fluorescence is enhanced upon reaction with cellular proteomes under conditions promoting accumulation of unfolded proteins. TPE-MI reactivity can be used to track which proteins expose more cysteine residues under stress through proteomic analysis. We show that TPE-MI can report imbalances in proteostasis in induced pluripotent stem cell models of Huntington disease, as well as cells transfected with mutant Huntington exon 1 before the formation of visible aggregates. TPE-MI also detects protein damage following dihydroartemisinin treatment of the malaria parasites Plasmodium falciparum. TPE-MI therefore holds promise as a tool to probe proteostasis mechanisms in disease.
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