The innate immune system in Parkinson′s disease: a novel target promoting endogenous neuroregeneration

Abstract

Parkinson's disease (PD) is a slowly progressing neurodegenerative disorder clinically defined by key symptoms like bradykinesia, rigidity, resting tremor, and postural instability. Reduction of dopaminergic terminals in the caudate nucleus and putamen, i.e., the striatum, accompanied by decreased striatal levels of dopamine, and most likely consecutive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are tightly linked to the onset of the motor symptoms. With the etiology of PD largely not yet well defined, there is accumulating evidence for increased immune activation in PD. The majority of studies favor a detrimental effect of microglia, the resident innate immune cells of the brain, on PD pathogenesis. In the presence of alpha-synuclein, inflammatory responses elicited by microglia may be initiated by pattern recognition receptors, e.g., toll-like receptors (TLR) leading to the distinct activation of signal transduction pathways. For instance, TLRs couple to signal adaptor proteins like myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF), resulting ultimately in the activation of multiple, signal-dependent transcription factors including members of the nuclear factor κB (NF-κB) or AP-1 families. This leads to an enhanced production of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) or IL-6 (Figure 1). Indeed, increased levels of pro-inflammatory mediators have been detected within the SNpc and striatum supporting the existence of an underlying neuroinflammatory signature in PD (see review by Hirsch and Hunot, 2009). As a consequence, these inflammatory mediators may directly or via astrocyte activation perturb neuronal homeostasis (Saijo et al., 2009). However, the precise temporal and spatial sequence of this immunogenic response during the course of PD is not defined yet.