title: Dithiol-based compounds maintain expression of antioxidant protein peroxiredoxin 1 that counteracts toxicity of mutant huntingtin.
abstract: Mitochondrial dysfunction and elevated reactive oxygen species are strongly implicated in both aging and various neurodegenerative disorders, including Huntington disease (HD). Because reactive oxygen species can promote the selective oxidation of protein cysteine sulfhydryl groups to disulfide bonds we examined the spectrum of disulfide-bonded proteins that were specifically altered in a HD context. Protein extracts from PC12 cells overexpressing the amino-terminal fragment of the Huntingtin (Htt) protein with either a nonpathogenic or pathogenic polyglutamine repeat (Htt-103Q) were resolved by redox two-dimensional PAGE followed by mass spectrometry analysis. Several antioxidant proteins were identified that exhibited changes in disulfide bonding unique to Htt-103Q expressing cells. In particular, the antioxidant protein peroxiredoxin 1 (Prx1) exhibited both decreased expression and hyperoxidation in response to mutant Htt expressed in either PC12 cells or immortalized striatal cells exposed to 3-nitropropionic acid. Ectopic expression of Prx1 in PC12 cells attenuated mutant Htt-induced toxicity. In contrast, short hairpin RNA-mediated knockdown of Prx1 potentiated mHtt toxicity. Furthermore, treatment with the dithiol-based compounds dimercaptopropanol and dimercaptosuccinic acid suppressed toxicity in both HD cell models, whereas monothiol compounds were relatively ineffective. Dimercaptopropanol treatment also prevented mutant Htt-induced loss of Prx1 expression in both cell models. Our studies reveal for the first time that pathogenic Htt can affect the expression and redox state of antioxidant proteins; an event countered by specific dithiol-based compounds. These findings should provide a catalyst to explore the use of dithiol-based drugs for the treatment of neurodegenerative diseases.
authors.affiliation: Department of Biology, University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pitts
authors.forename: Kyle
authors.initials: K
authors.lastname: Dailey
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Newington
authors.forename: Andrew
authors.initials: A
authors.lastname: Chien
authors.forename: Robert
authors.initials: R
authors.lastname: Arseneault
authors.forename: Tyler
authors.initials: T
authors.lastname: Cann
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
authors.forename: Robert C
authors.initials: RC
authors.lastname: Cumming
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000166:cytology; D004220:Disulfides / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D010455:Peptides / Q000378:metabolism; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D004220:Disulfides; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C097188:polyglutamine; D014050:Toluene; C489898:Prdx1 protein, rat; D054464:Peroxiredoxins; C004848:dithiol