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

Abstract

BackgroundMounting 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.MethodsBased 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.ResultsOur 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.ConclusionsOur 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.

Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease

“…Recent data also indicate that TLR4 is up-regulated by MPTP treatment in a mouse model of PD6, may promote alpha-synuclein clearance in a model of atypical parkinsonism7 and that alpha-synuclein directly activates microglia, inciting the production of proinflammatory molecules and altering the expression of TLRs89. Finally, MyD88 deletion protects against MPTP neurotoxicity, albeit only in the enteric and not in the central nervous system1011.…”

Impact of intravenous immunoglobulin on the dopaminergic system and immune response in the acute MPTP mouse model of Parkinson’s disease

“…The total number of TH-positive and TH-negative neurons of the SNpc was quantified stereologically on seven sections of a 1/5 series, as previously described [48-50]. Selected sections, at intervals of 125 μm, were counted in a blinded fashion by two independent investigators using Stereo Investigator software (MicroBrightfield, Williston, VT, USA) integrated to an E800 Nikon 274 microscope.…”

Cystamine/cysteamine rescues the dopaminergic system and shows neurorestorative properties in an animal model of Parkinson's disease

“…Every fifth section (for TH, NeuN, GFAP and IbaI) and every tenth section (for DAT and TH/Lmx1b) throughout the SNpc (AP: levels of −2.75 mm to −3.58 mm (Allen, 2008)) were analysed using the Stereo investigator software (MicroBrightfield) integrated to a E800 Nikon microscope (Nikon Canada Inc.) (Drouin-Ouellet et al, 2011b;Gibrat et al, 2009).…”

“…Mice were tested before treatment begun (3 or 5 weeks post-surgery), 3 weeks following the initiation of treatment and 5-hydroxytryptamine (5HT) concentration were measured by HPLC coupled with electrochemical detection (Bousquet et al, 2011;2008). Each striatal sample comprised ten 20-µm thick cryostat sections ranging between AP: +0.945 mm and +0.020 mm (Allen, 2008) and was processed and analysed as previously described (Bousquet et al, 2011;Drouin-Ouellet et al, 2011b).…”