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

Authors :
Calon Frédéric
Bousquet Mélanie
Gibrat Claire
Drouin-Ouellet Janelle
Kriz Jasna
Cicchetti Francesca
Source :
Journal of Neuroinflammation, Vol 8, Iss 1, p 137 (2011)
Publication Year :
2011
Publisher :
BMC, 2011.

Abstract

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.

Details

Language :
English
ISSN :
17422094
Volume :
8
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Journal of Neuroinflammation
Publication Type :
Academic Journal
Accession number :
edsdoj.54526090c40749a58b22a4ff396497bb
Document Type :
article
Full Text :
https://doi.org/10.1186/1742-2094-8-137