title: The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration.
abstract: BACKGROUND
  Mounting evidence supports a significant role of inflammation in Parkinson's disease (PD) pathophysiology, with several inflammatory pathways being suggested as playing a role in the dopaminergic degeneration seen in humans and animal models of the disease. These include tumor necrosis factor, prostaglandins and oxidative-related stress components. However, the role of innate immunity has not been established in PD.
  
  
  METHODS
  Based on the fact that the myeloid differentiation primary response gene (88) (MyD88) is the most common adaptor protein implicated in toll-like receptor (TLR) signaling, critical in the innate immune response, we undertook a study to investigate the potential contribution of this specific pathway to MPTP-induced brain dopaminergic degeneration using MyD88 knock out mice (MyD88-/-), following our observations that the MyD88-dependent pathway was critical for MPTP dopaminergic toxicity in the enteric nervous system. Post-mortem analyses assessing nigrostriatal dopaminergic degeneration and inflammation were performed using HPLC, western blots, autoradiography and immunofluorescence.
  
  
  RESULTS
  Our results demonstrate that MyD88-/- mice are as vulnerable to MPTP-induced dopamine and DOPAC striatal depletion as wild type mice. Furthermore, MyD88-/- mice show similar striatal dopamine transporter and tyrosine hydroxylase loss, as well as dopaminergic cell loss in the substantia nigra pars compacta in response to MPTP. To evaluate the extent of the inflammatory response created by the MPTP regimen utilized, we further performed bioluminescence imaging using TLR2-luc/gfp transgenic mice and microglial density analysis, which revealed a modest brain microglial response following MPTP. This was accompanied by a significant astrocytic reaction in the striatum, which was of similar magnitude both in wild type and MyD88-/- mice.
  
  
  CONCLUSIONS
  Our results suggest that subacute MPTP-induced dopaminergic degeneration observed in the central nervous system is MyD88-independent, in contrast to our recent observations that this pathway, in the same cohort of animals, is critical in the loss of dopaminergic neurons in the enteric nervous system.
authors: Axe Neurosciences, Centre de Recherche du CHUL (CHUQ), T2-50, 2705 Boulevard Laurier, Québec, G1V 4G2, Canada.
authors: Janelle
authors: J
authors: Drouin-Ouellet
authors: Claire
authors: C
authors: Gibrat
authors: Mélanie
authors: M
authors: Bousquet
authors: Frédéric
authors: F
authors: Calon
authors: Jasna
authors: J
authors: Kriz
authors: Francesca
authors: F
authors: Cicchetti
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001345:Autoradiography; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009498:Neurotoxins; D051193:Toll-Like Receptors; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine