Molecular Neurobiology

, Volume 53, Issue 8, pp 5229–5251 | Cite as

Inhibition of Protein Ubiquitination by Paraquat and 1-Methyl-4-Phenylpyridinium Impairs Ubiquitin-Dependent Protein Degradation Pathways

  • Juliana Navarro-Yepes
  • Annadurai Anandhan
  • Erin Bradley
  • Iryna Bohovych
  • Bo Yarabe
  • Annemieke de Jong
  • Huib Ovaa
  • You Zhou
  • Oleh Khalimonchuk
  • Betzabet Quintanilla-Vega
  • Rodrigo Franco
Article

Abstract

Intracytoplasmic inclusions of protein aggregates in dopaminergic cells (Lewy bodies) are the pathological hallmark of Parkinson’s disease (PD). Ubiquitin (Ub), alpha (α)-synuclein, p62/sequestosome 1, and oxidized proteins are the major components of Lewy bodies. However, the mechanisms involved in the impairment of misfolded/oxidized protein degradation pathways in PD are still unclear. PD is linked to mitochondrial dysfunction and environmental pesticide exposure. In this work, we evaluated the effects of the pesticide paraquat (PQ) and the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+) on Ub-dependent protein degradation pathways. No increase in the accumulation of Ub-bound proteins or aggregates was observed in dopaminergic cells (SK-N-SH) treated with PQ or MPP+, or in mice chronically exposed to PQ. PQ decreased Ub protein content, but not its mRNA transcription. Protein synthesis inhibition with cycloheximide depleted Ub levels and potentiated PQ-induced cell death. The inhibition of proteasomal activity by PQ was found to be a late event in cell death progression and had neither effect on the toxicity of either MPP+ or PQ, nor on the accumulation of oxidized sulfenylated, sulfonylated (DJ-1/PARK7 and peroxiredoxins), and carbonylated proteins induced by PQ. PQ- and MPP+-induced Ub protein depletion prompted the dimerization/inactivation of the Ub-binding protein p62 that regulates the clearance of ubiquitinated proteins by autophagy. We confirmed that PQ and MPP+ impaired autophagy flux and that the blockage of autophagy by the overexpression of a dominant-negative form of the autophagy protein 5 (dnAtg5) stimulated their toxicity, but there was no additional effect upon inhibition of the proteasome. PQ induced an increase in the accumulation of α-synuclein in dopaminergic cells and membrane-associated foci in yeast cells. Our results demonstrate that the inhibition of protein ubiquitination by PQ and MPP+ is involved in the dysfunction of Ub-dependent protein degradation pathways.

Keywords

Ubiquitin-proteasome system Sequestosome 1 SQSTM1 MPP+ Ubiquitylation Autophagy Pesticides Parkinson’s disease 

Supplementary material

12035_2015_9414_MOESM1_ESM.pdf (283 kb)
ESM 1(PDF 283 kb)

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© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Juliana Navarro-Yepes
    • 1
    • 2
    • 4
  • Annadurai Anandhan
    • 1
    • 2
  • Erin Bradley
    • 1
  • Iryna Bohovych
    • 1
    • 3
  • Bo Yarabe
    • 1
  • Annemieke de Jong
    • 5
  • Huib Ovaa
    • 5
  • You Zhou
    • 3
  • Oleh Khalimonchuk
    • 1
    • 3
  • Betzabet Quintanilla-Vega
    • 4
  • Rodrigo Franco
    • 1
    • 2
  1. 1.Redox Biology CenterUniversity of Nebraska-LincolnLincolnUSA
  2. 2.School of Veterinary Medicine and Biomedical SciencesUniversity of Nebraska-LincolnLincolnUSA
  3. 3.Department of BiochemistryUniversity of Nebraska-LincolnLincolnUSA
  4. 4.Department of ToxicologyCINVESTAV-IPNMexico CityMexico
  5. 5.Division of Cell Biology IIThe Netherlands Cancer InstituteAmsterdamThe Netherlands

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