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Inhibition of Excessive Oxidative Protein Folding Is Protective in MPP+ Toxicity-Induced Parkinson's Disease Models
Lehtonen S.1; Jaronen M.1; Vehvilainen P.1; Lakso M.1; Rudgalvyte M.1; Keksa-Goldsteine V.1; Wong G.1; Courtney M.J.1; Koistinaho J.1; Goldsteins G.1
2016-09-10
Source PublicationAntioxidants and Redox Signaling
ISSN15577716 15230864
Volume25Issue:8Pages:485-497
Abstract

Aims: Protein misfolding occurs in neurodegenerative diseases, including Parkinson's disease (PD). In endoplasmic reticulum (ER), an overload of misfolded proteins, particularly alpha-synuclein (αSyn) in PD, may cause stress and activate the unfolded protein response (UPR). This UPR includes activation of chaperones, such as protein disulphide isomerase (PDI), which assists refolding and contributes to removal of unfolded proteins. Although up-regulation of PDI is considered a protective response, its activation is coupled with increased activity of ER oxidoreductin 1 (Ero1), producing harmful hydroperoxide. The objective of this study was to assess whether inhibition of excessive oxidative folding protects against neuronal death in well-established 1-methyl-4-phenylpyridinium (MPP) models of PD. Results: We found that the MPP neurotoxicity and accumulation of αSyn in the ER are prevented by inhibition of PDI or Ero1α. The MPP neurotoxicity was associated with a reductive shift in the ER, an increase in the reduced form of PDI, an increase in intracellular Ca, and an increase in Ca-sensitive calpain activity. All these MPP-induced changes were abolished by inhibiting PDI. Importantly, inhibition of PDI resulted in increased autophagy, and it prevented MPP-induced death of dopaminergic neurons in Caenorhabditis elegans. Innovation and Conclusion: Our data indicate that although inhibition of PDI suppresses excessive protein folding and ER stress, it induces clearance of aggregated αSyn by autophagy as an alternative degradation pathway. These findings suggest a novel model explaining the contribution of ER dysfunction to MPP-induced neurodegeneration and highlight PDI inhibitors as potential treatment in diseases involving protein misfolding. Antioxid.

DOI10.1089/ars.2015.6402
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS SubjectBiochemistry & Molecular Biology ; Endocrinology & Metabolism
WOS IDWOS:000382304300002
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Cited Times [WOS]:9   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Itä-Suomen yliopisto
2.Universidade de Macau
Recommended Citation
GB/T 7714
Lehtonen S.,Jaronen M.,Vehvilainen P.,et al. Inhibition of Excessive Oxidative Protein Folding Is Protective in MPP+ Toxicity-Induced Parkinson's Disease Models[J]. Antioxidants and Redox Signaling,2016,25(8):485-497.
APA Lehtonen S..,Jaronen M..,Vehvilainen P..,Lakso M..,Rudgalvyte M..,...&Goldsteins G..(2016).Inhibition of Excessive Oxidative Protein Folding Is Protective in MPP+ Toxicity-Induced Parkinson's Disease Models.Antioxidants and Redox Signaling,25(8),485-497.
MLA Lehtonen S.,et al."Inhibition of Excessive Oxidative Protein Folding Is Protective in MPP+ Toxicity-Induced Parkinson's Disease Models".Antioxidants and Redox Signaling 25.8(2016):485-497.
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