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The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration

Drouin-Ouellet, Janelle LU ; Gibrat, Claire; Bousquet, Mélanie; Calon, Frédéric; Kriz, Jasna and Cicchetti, Francesca (2011) In Journal of Neuroinflammation 8. p.1-12
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... (More)

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.

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keywords
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 3,4-Dihydroxyphenylacetic Acid, Animals, Astrocytes, Autoradiography, Corpus Striatum, Dopamine, Dopaminergic Neurons, Glial Fibrillary Acidic Protein, Humans, MPTP Poisoning, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Neurotoxins, Signal Transduction, Substantia Nigra, Toll-Like Receptors, Journal Article, Research Support, Non-U.S. Gov't
in
Journal of Neuroinflammation
volume
8
pages
1 - 12
publisher
BioMed Central
external identifiers
  • scopus:80053634031
ISSN
1742-2094
DOI
10.1186/1742-2094-8-137
language
English
LU publication?
no
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f17ec679-43d5-468f-b6ae-fdb85c0076fc
date added to LUP
2016-11-22 09:05:14
date last changed
2017-11-17 09:24:56
@article{f17ec679-43d5-468f-b6ae-fdb85c0076fc,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>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.</p>},
  articleno    = {137},
  author       = {Drouin-Ouellet, Janelle and Gibrat, Claire and Bousquet, Mélanie and Calon, Frédéric and Kriz, Jasna and Cicchetti, Francesca},
  issn         = {1742-2094},
  keyword      = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine,3,4-Dihydroxyphenylacetic Acid,Animals,Astrocytes,Autoradiography,Corpus Striatum,Dopamine,Dopaminergic Neurons,Glial Fibrillary Acidic Protein,Humans,MPTP Poisoning,Mice,Mice, Inbred C57BL,Mice, Knockout,Myeloid Differentiation Factor 88,Neurotoxins,Signal Transduction,Substantia Nigra,Toll-Like Receptors,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {10},
  pages        = {1--12},
  publisher    = {BioMed Central},
  series       = {Journal of Neuroinflammation},
  title        = {The role of the MYD88-dependent pathway in MPTP-induced brain dopaminergic degeneration},
  url          = {http://dx.doi.org/10.1186/1742-2094-8-137},
  volume       = {8},
  year         = {2011},
}