title: Analysis of inflammation-related nigral degeneration and locomotor function in DJ-1(-/-) mice.
abstract: BACKGROUND
  Complex interactions involving genetic susceptibility and environmental factors are thought to underlie the pathogenesis of Parkinson's disease (PD). Although the role of inflammatory processes in modulating risk for development of PD has yet to be fully understood, prospective studies suggest that chronic use of NSAIDs reduce the incidence of PD. Loss-of-function mutations in the DJ-1 gene cause a rare form of familial PD with an autosomal recessive pattern of inheritance; however, DJ-1-/- mice do not display nigrostriatal pathway degeneration, suggesting that additional factors such as inflammation may be needed to induce neurodegeneration on the background of DJ-1 gene mutations. Neuroinflammation causes oxidative stress and, based on evidence that DJ-1 plays a protective role against oxidative stress, we investigated whether DJ-1-/- mice display increased vulnerability to inflammation-induced nigral degeneration.
  
  
  METHODS
  We exposed adult wild-type and DJ-1-/- mice to repeated intranasal administration of soluble TNF (inTNF) or repeated intraperitoneal injections of low-dose lipopolysaccharide (LPS) or saline vehicle. We measured locomotor performance using a variety of behavior tasks, striatal dopamine (DA) content by HPLC, DA neuron (TH+ cells) and total neuron (NeuN+ cells) number in the substantia nigra pars compacta and ventral tegmental area by unbiased stereology, number of Iba1-positive microglia, and mRNA levels of inflammatory and oxidative stress genes by quantitative PCR in the midbrain, cortex and isolated peritoneal macrophages of DJ-1-/- and wild-type mice.
  
  
  RESULTS
  We found that chronic LPS injections induced similar neuroinflammatory responses in the midbrains of DJ-1-/- mice and wild-type mice and neither group developed locomotor deficits or nigral degeneration. inTNF administration did not appear to induce neuroinflammatory responses in LPS-treated wild-type or DJ-1-/- mice. The lack of vulnerability to inflammation-induced nigral degeneration was not due to enhanced anti-oxidant gene responses in the midbrains of DJ-1-/- mice which, in fact, displayed a blunted response relative to that of wild-type mice. Peripheral macrophages from wild-type and DJ-1-/- mice displayed similar basal and LPS-induced inflammatory and oxidative stress markers in vitro.
  
  
  CONCLUSIONS
  Our studies indicate that DJ-1-/- mice do not display increased vulnerability to inflammation-related nigral degeneration in contrast to what has been reported for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. We conclude that either DJ-1 does not have a critical role in protecting DA neurons against inflammation-induced oxidative stress and/or there is compensatory gene expression in the midbrain of DJ-1-/- mice that renders them resistant to the cytotoxic effects triggered by chronic peripheral inflammation.
authors.affiliation: Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Thi A
authors.initials: TA
authors.lastname: Nguyen
authors.forename: Tamy
authors.initials: T
authors.lastname: Frank-Cannon
authors.forename: Terina N
authors.initials: TN
authors.lastname: Martinez
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Ruhn
authors.forename: Marian
authors.initials: M
authors.lastname: Marvin
authors.forename: Bradford
authors.initials: B
authors.lastname: Casey
authors.forename: Isaac
authors.initials: I
authors.lastname: Treviño
authors.forename: John J
authors.initials: JJ
authors.lastname: Hong
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Malú G
authors.initials: MG
authors.lastname: Tansey
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology*; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D054464:Peroxiredoxins; D004856:Postural Balance / Q000187:drug effects; D000071617:Protein Deglycase DJ-1; D011597:Psychomotor Performance / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D013378:Substantia Nigra / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D015513:Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D054464:Peroxiredoxins; D014446:Tyrosine 3-Monooxygenase; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D004298:Dopamine