title: Paraquat Induces Peripheral Myelin Disruption and Locomotor Defects: Crosstalk with LXR and Wnt Pathways.
abstract: OBJECTIVE
  Paraquat (PQT), a redox-active herbicide, is a free radical-producing molecule, causing damage particularly to the nervous system; thus, it is employed as an animal model for Parkinson's disease. However, its impact on peripheral nerve demyelination is still unknown. Our aim is to decipher the influence of PQT-induced reactive oxygen species (ROS) production on peripheral myelin.
  
  
  RESULTS
  We report that PQT provokes severe locomotor and sensory defects in mice. PQT elicited an oxidative stress in the nerve, resulting in an increase of lipid peroxidation and protein carbonylation, despite the induction of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant defenses. We observed a dramatic disorganization of myelin sheaths in the sciatic nerves, dysregulation of myelin gene expression, and aggregation of myelin proteins, a hallmark of demyelination. PQT altered myelin gene expression via liver X receptor (LXR) signaling, a negative regulator of peripheral myelin gene expression through its dialog with the Wnt/β-catenin pathway. PQT prevented β-catenin binding on myelin gene promoters, resulting in the inhibition of Wnt/β-catenin-dependent myelin gene expression. Wnt pathway activation by LiCl dampened the deleterious effects of PQT. LiCl blocked PQT-induced oxidative stress and reduced Schwann cell death. LiCl+PQT-treated mice had normal sensorimotor behaviors and a usual nerve structure.
  
  
  METHODS
  We reveal that PQT damages the sciatic nerve by generating an oxidative stress, dysregulating LXR and Wnt/β-catenin pathways. The activation of Wnt signaling by LiCl reduced the deleterious effects of PQT on the nerve.
  
  
  CONCLUSIONS
  We demonstrate that PQT instigates peripheral nerve demyelinating neuropathies by enhancing ROS production and deregulating LXR and Wnt pathways. Stimulating Wnt pathway could be a therapeutic strategy for neuropathy treatment. Antioxid. Redox Signal. 27, 168-183.
authors: 1 INSERM UMR-S 1124, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, Paris Descartes University , Paris, France .
authors: Mehdi
authors: M
authors: Hichor
authors: 1 INSERM UMR-S 1124, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, Paris Descartes University , Paris, France .
authors: Nirmal Kumar
authors: NK
authors: Sampathkumar
authors: 1 INSERM UMR-S 1124, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, Paris Descartes University , Paris, France .
authors: Julia
authors: J
authors: Montanaro
authors: 1 INSERM UMR-S 1124, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, Paris Descartes University , Paris, France .
authors: Didier
authors: D
authors: Borderie
authors: 1 INSERM UMR-S 1124, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, Paris Descartes University , Paris, France .
authors: Patrice X
authors: PX
authors: Petit
authors: 2 INSERM UMRS-S 1130, CNRS UMR824, Pierre and Marie Curie University , Paris, France .
authors: Victor
authors: V
authors: Gorgievski
authors: 2 INSERM UMRS-S 1130, CNRS UMR824, Pierre and Marie Curie University , Paris, France .
authors: Eleni T
authors: ET
authors: Tzavara
authors: 3 Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon .
authors: Assaad A
authors: AA
authors: Eid
authors: 1 INSERM UMR-S 1124, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, Paris Descartes University , Paris, France .
authors: Frédéric
authors: F
authors: Charbonnier
authors: 1 INSERM UMR-S 1124, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, Paris Descartes University , Paris, France .
authors: Julien
authors: J
authors: Grenier
authors: 1 INSERM UMR-S 1124, Sorbonne Paris Cité, Faculté des Sciences Fondamentales et Biomédicales, Paris Descartes University , Paris, France .
authors: Charbel
authors: C
authors: Massaad
mesh_terms: D000818:Animals; D002460:Cell Line; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006540:Herbicides / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D000071518:Liver X Receptors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009185:Myelin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D010269:Paraquat / Q000633:toxicity*; D066263:Protein Aggregation, Pathological; D050050:Protein Carbonylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D006540:Herbicides; D000071518:Liver X Receptors; D009185:Myelin Proteins; D017382:Reactive Oxygen Species; D010269:Paraquat
keywords: LXR; Wnt/β-catenin; myelin; oxidative stress; paraquat; peripheral neuropathy