Abstract
BackgroundIn Parkinson’s disease (PD), loss of striatal dopaminergic (DA) terminals and degeneration of DA neurons in the substantia nigra (SN) are associated with inflammation. Nucleotide-binding oligomerization domain-containing protein (NOD)2, one of the first discovered NOD-like receptors, plays an important role in inflammation. However, the role of NOD2 has not been elucidated in PD.MethodsNOD2 mRNA and protein expression in the SN and the striatum of C57BL/6 mice treated with 6-hydroxydopamine (6-OHDA) was measured. We next investigated the potential contribution of the NOD2-dependent pathway to 6-OHDA-induced DA degeneration using NOD2-deficient (NOD2−/−) mice. Assays examining DA degeneration and inflammation include HPLC, Western blot, immunohistochemistry, TUNEL staining, and cytometric bead array. To further explore a possible link between NADPH oxidase 2 (NOX2) and NOD2 signaling in PD, microglia were transfected with shRNA specific to NOX2 in vitro and apocynin were given to mice subjected to 6-OHDA and muramyl dipeptide (MDP) striatal injection.ResultsThe expression of NOD2 was upregulated in an experimental PD model induced by the neurotoxin 6-OHDA. NOD2 deficiency resulted in a protective effect against 6-OHDA-induced DA degeneration and neuronal death, which was associated with the attenuated inflammatory response. Moreover, silencing of NOX2 in microglia suppressed the expression of NOD2 and the inflammatory response induced by 6-OHDA and attenuated the toxicity of conditioned medium from 6-OHDA or MDP-stimulated microglia to neuronal cells. Furthermore, apocynin treatment inhibited NOD2 upregulation and DA degeneration in the SN of WT mice induced by 6-OHDA and MDP.ConclusionThis study provides the direct evidence that NOD2 is related to 6-OHDA-induced DA degeneration through NOX2-mediated oxidative stress, indicating NOD2 is a novel innate immune signaling molecule participating in PD inflammatory response.
Highlights
In Parkinson’s disease (PD), loss of striatal dopaminergic (DA) terminals and degeneration of DA neurons in the substantia nigra (SN) are associated with inflammation
Striatal injections Mice were placed in a stereotaxic device under 1.5% pentobarbital sodium anesthesia and given 2 μl of 3 μg/ μl 6-OHDA (Sigma-Aldrich, H4381) which is dissolved in sterile normal saline (NS) with 0.02% ascorbic acid or 4 μg/μl muramyl dipeptide (MDP) solution into two different sites of the right striatum (STR) separately: point A—1.0 mm anterior and 2.1 mm lateral to the bregma and 2.9 mm from the dura mater; point B—0.3 mm posterior and 2.3 mm lateral to the bregma and 2.9 mm from the dura mater
NADPH oxidase 2 (NOX2) was activated in PD mice induced by 6-OHDA In order to investigate how Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is activated in PD, we examined the expression of NADPH oxidase subunit NOX2 and Reactive oxygen species (ROS) production in the SN at indicated time points after the injection of 6-OHDA
Summary
In Parkinson’s disease (PD), loss of striatal dopaminergic (DA) terminals and degeneration of DA neurons in the substantia nigra (SN) are associated with inflammation. Nucleotide-binding oligomerization domaincontaining protein (NOD), one of the first discovered NOD-like receptors, plays an important role in inflammation. Accumulating evidence suggests that activation of innate immunity via Toll-like receptors (TLRs) [13,14,15,16,17,18,19] and nucleotide-binding oligomerization domaincontaining protein (NOD)-like receptors (NLRs) [20, 21] has been implied to participate in the pathogenesis of PD. NOD2, one of the first discovered NLRs, plays an important role in regulating inflammatory homeostasis. It recognizes the exogenous pathogen-associated molecular patterns (PAMPs) such as muramyl dipeptide (MDP), a degradation product of peptidoglycans from virtually all bacteria [22], and endogenous danger-associated molecular patterns (DAMPs) which are released from the damaged tissues following cellular stress. This study was designed to elucidate the function of NOD2 signaling and its regulatory mechanism in the pathogenesis of PD
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