title: Inhibition of Excessive Oxidative Protein Folding Is Protective in MPP(+) Toxicity-Induced Parkinson's Disease Models.
abstract: 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.
  
  
  
  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(2+), and an increase in Ca(2+)-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.
  
  
  
  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. Redox Signal. 25, 485-497.
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Šárka
authors.initials: Š
authors.lastname: Lehtonen
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Merja
authors.initials: M
authors.lastname: Jaronen
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Piia
authors.initials: P
authors.lastname: Vehviläinen
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Merja
authors.initials: M
authors.lastname: Lakso
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Martina
authors.initials: M
authors.lastname: Rudgalvyte
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Velta
authors.initials: V
authors.lastname: Keksa-Goldsteine
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .|2 Faculty of Health Sciences, University of Macau , Macau, China .
authors.forename: Garry
authors.initials: G
authors.lastname: Wong
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Courtney
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.affiliation: 1 Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland , Kuopio, Finland .
authors.forename: Gundars
authors.initials: G
authors.lastname: Goldsteins
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D001343:Autophagy; D001414:Bacitracin / Q000494:pharmacology; D017173:Caenorhabditis elegans; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D059290:Dopaminergic Neurons / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006540:Herbicides / Q000633:toxicity; D006801:Humans; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D056811:Unfolded Protein Response; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D006540:Herbicides; D051844:alpha-Synuclein; D001414:Bacitracin; D010088:Oxidoreductases; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium