Cysteine oxidation within N-terminal mutant huntingtin promotes oligomerization and delays clearance of soluble protein.

Fox, Jonathan H.; Connor, Teal; Stiles, Megan; Kama, Jibrin; Zhang, Lu; Dorsey, Kathryn; Lieberman, Gregory; Sapp, Ellen; Cherny, Robert A.; Banks, M. M.; Volitakis, Irene; DiFiglia, Marian; Berezovska, Oksana; Bush, Ashley I.; Hersch, Steven M.

doi:10.1074/jbc.a110.199448

Cited by 3 publications

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“…Cys106 is subject to modification during oxidative stress, and its oxidation has been proposed to be an important post-translational modification that may allow DJ-1 to act as a cellular redox sensor or to regulate interactions with its binding partners. , However, the detailed mechanism by which cysteine oxidation alters DJ-1 function is unclear, particularly because the crystal structures of the reduced and Cys106-SO 2 – proteins are essentially identical. , Our results show that both the human and insect proteins are substantially stabilized by oxidation of the reactive cysteine to the cysteine-sulfinate. The stabilization contrasts with many other proteins where cysteine oxidation to the sulfinate or sulfonate is associated with destabilization. , When considered in the context of previous evidence that oxidation of Cys106 in human DJ-1 leads to protein destabilization, our observations strongly suggest that it is the formation of the more highly oxidized cysteine-sulfonate (Cys106-SO 3 – ) that disrupts DJ-1 stability. This is consistent with some previously proposed models , and indicates that DJ-1 stability is biphasically regulated by oxidative cysteine modification.…”

Section: Discussionmentioning

confidence: 52%

“…The stabilization contrasts with many other proteins where cysteine oxidation to the sulfinate or sulfonate is associated with destabilization. 71,72 When considered in the context of previous evidence that oxidation of Cys106 in human DJ-1 leads to protein destabilization, 39 our observations strongly suggest that it is the formation of the more highly oxidized cysteine-sulfonate (Cys106-SO 3…”

Section: ■ Discussionmentioning

confidence: 79%

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Conservation of Oxidative Protein Stabilization in an Insect Homologue of Parkinsonism-Associated Protein DJ-1

2012

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DJ-1 is a conserved, disease-associated protein that protects against oxidative stress and mitochondrial damage in multiple organisms. Human DJ-1 contains a functionally essential cysteine residue (Cys106) whose oxidation is important for regulating protein function by an unknown mechanism. This residue is well conserved in other DJ-1 homologues, including two (DJ-1α and DJ-1β) in Drosophila melanogaster. Because D. melanogaster is a powerful model system for studying DJ-1 function, we have determined the crystal structure and impact of cysteine oxidation on Drosophila DJ-1β. The structure of D. melanogaster DJ-1β is similar to that of human DJ-1, although two important residues in the human protein, Met26 and His126, are not conserved in DJ-1β. His126 in human DJ-1 is substituted with a tyrosine in DJ-1β, and this residue is not able to compose a putative catalytic dyad with Cys106 that was proposed to be important in the human protein. The reactive cysteine in DJ-1 is oxidized readily to the cysteine-sulfinic acid in both flies and humans and this may regulate the cytoprotective function of the protein. We show that the oxidation of this conserved cysteine residue to its sulfinate form (Cys-SO2−) results in considerable thermal stabilization of both Drosophila DJ-1β and human DJ-1. Therefore, protein stabilization is one potential mechanism by which cysteine oxidation may regulate DJ-1 function in vivo. More generally, most close DJ-1 homologues are likely stabilized by cysteine-sulfinic acid formation but destabilized by further oxidation, suggesting that they are biphasically regulated by oxidative modification.

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Section: Discussionmentioning

confidence: 52%

Section: ■ Discussionmentioning

confidence: 79%

Conservation of Oxidative Protein Stabilization in an Insect Homologue of Parkinsonism-Associated Protein DJ-1

2012

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“…This is consistent with other suggestions of altered one‐carbon metabolism, such as the increases in DNA and histone methylation . Since there is normally an equilibrium between methionine and cysteine, this finding could also be connected to alterations in L‐cysteine levels that have been reported in HD and related to oxidative mechanisms of pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

A systems‐level “misunderstanding”: the plasma metabolome in Huntington's disease

Rosas

Doros

Bhasin

et al. 2015

Ann Clin Transl Neurol

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ObjectiveHuntington’s disease (HD) is a rare neurodegenerative disease caused by the expansion of an N-terminal repeat in the huntingtin protein. The protein is expressed in all cells in the body; hence, peripheral tissues, such as blood, may recapitulate processes in the brain. The plasma metabolome may provide a window into active processes that influence brain health and a unique opportunity to noninvasively identify processes that may contribute to neurodegeneration. Alterations in metabolic pathways in brain have been shown to profoundly impact HD. Therefore, identification and quantification of critical metabolomic perturbations could provide novel biomarkers for disease onset and disease progression.MethodsWe analyzed the plasma metabolomic profiles from 52 premanifest (PHD), 102 early symptomatic HD, and 140 healthy controls (NC) using liquid chromatography coupled with a highly sensitive electrochemical detection platform.ResultsAlterations in tryptophan, tyrosine, purine, and antioxidant pathways were identified, including many related to energetic and oxidative stress and derived from the gut microbiome. Multivariate statistical modeling demonstrated mutually distinct metabolomic profiles, suggesting that the processes that determine onset were likely distinct from those that determine progression. Gut microbiome-derived metabolites particularly differentiated the PHD metabolome, while the symptomatic HD metabolome was increasingly influenced by metabolites that may reflect mutant huntingtin toxicity and neurodegeneration.InterpretationUnderstanding the complex changes in the delicate balance of the metabolome and the gut microbiome in HD, and how they relate to disease onset, progression, and phenotypic variability in HD are critical questions for future research.

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“…Disruption of metal homeostasis in the progression of HD has been identified, with increased iron levels observed in the striatum (Bartzokis et al., ), and copper levels are also increased in the CNS of human HD brains, HD animal models (Dexter et al., , ; Perez et al., ; Fox et al., ). In vitro studies show that the fragment containing the first 171 amino acids of human wild‐type Htt and its glutamine‐expanded mutant form directly interacts with and reduces copper and iron (Fox et al., , ). While Htt protein has yet to be inconclusively identified in EVs, several proteomic studies have identified Htt in exosomes via mass spectrometry (Miguet et al., ; Wang et al., ; Fraser et al., ; Meckes et al., ; Skogberg et al., ).…”

Section: Introductionmentioning

confidence: 99%

The secret life of extracellular vesicles in metal homeostasis and neurodegeneration

Bellingham

Guo

Hill

2015

Biology of the Cell

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Biologically active metals such as copper, zinc and iron are fundamental for sustaining life in different organisms with the regulation of cellular metal homeostasis tightly controlled through proteins that coordinate metal uptake, efflux and detoxification. Many of the proteins involved in either uptake or efflux of metals are localised and function on the plasma membrane, traffic between intracellular compartments depending upon the cellular metal environment and can undergo recycling via the endosomal pathway. The biogenesis of exosomes also occurs within the endosomal system, with several major neurodegenerative disease proteins shown to be released in association with these vesicles, including the amyloid-β (Aβ) peptide in Alzheimer's disease and the infectious prion protein involved in Prion diseases. Aβ peptide and the prion protein also bind biologically active metals and are postulated to play important roles in metal homeostasis. In this review, we will discuss the role of extracellular vesicles in Alzheimer's and Prion diseases and explore their potential contribution to metal homeostasis.

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Cysteine oxidation within N-terminal mutant huntingtin promotes oligomerization and delays clearance of soluble protein.

Cited by 3 publications

References 0 publications

Conservation of Oxidative Protein Stabilization in an Insect Homologue of Parkinsonism-Associated Protein DJ-1

Conservation of Oxidative Protein Stabilization in an Insect Homologue of Parkinsonism-Associated Protein DJ-1

A systems‐level “misunderstanding”: the plasma metabolome in Huntington's disease

The secret life of extracellular vesicles in metal homeostasis and neurodegeneration

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