Microglia Polarization, Gene-Environment Interactions and Wnt/β-Catenin Signaling: Emerging Roles of Glia-Neuron and Glia-Stem/Neuroprogenitor Crosstalk for Dopaminergic Neurorestoration in Aged Parkinsonian Brain.

Francesca L'Episcopo,Salvatore Caniglia,Nunzio Iraci,Bianca Marchetti,Maria F Serapide,Cataldo Tirolo,Silvia Vivarelli,Stefano Pluchino,Loredana Leggio,Nunzio Testa

doi:10.3389/fnagi.2018.00012

Abstract

Neuroinflammatory processes are recognized key contributory factors in Parkinson's disease (PD) physiopathology. While the causes responsible for the progressive loss of midbrain dopaminergic (mDA) neuronal cell bodies in the subtantia nigra pars compacta are poorly understood, aging, genetics, environmental toxicity, and particularly inflammation, represent prominent etiological factors in PD development. Especially, reactive astrocytes, microglial cells, and infiltrating monocyte-derived macrophages play dual beneficial/harmful effects, via a panel of pro- or anti-inflammatory cytokines, chemokines, neurotrophic and neurogenic transcription factors. Notably, with age, microglia may adopt a potent neurotoxic, pro-inflammatory “primed” (M1) phenotype when challenged with inflammatory or neurotoxic stimuli that hamper brain's own restorative potential and inhibit endogenous neurorepair mechanisms. In the last decade we have provided evidence for a major role of microglial crosstalk with astrocytes, mDA neurons and neural stem progenitor cells (NSCs) in the MPTP- (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-) mouse model of PD, and identified Wnt/β-catenin signaling, a pivotal morphogen for mDA neurodevelopment, neuroprotection, and neuroinflammatory modulation, as a critical actor in glia-neuron and glia-NSCs crosstalk. With age however, Wnt signaling and glia-NSC-neuron crosstalk become dysfunctional with harmful consequences for mDA neuron plasticity and repair. These findings are of importance given the deregulation of Wnt signaling in PD and the emerging link between most PD related genes, Wnt signaling and inflammation. Especially, in light of the expanding field of microRNAs and inflammatory PD-related genes as modulators of microglial-proinflammatory status, uncovering the complex molecular circuitry linking PD and neuroinflammation will permit the identification of new druggable targets for the cure of the disease. Here we summarize recent findings unveiling major microglial inflammatory and oxidative stress pathways converging in the regulation of Wnt/β-catenin signaling, and reciprocally, the ability of Wnt signaling pathways to modulate microglial activation in PD. Unraveling the key factors and conditons promoting the switch of the proinflammatory M1 microglia status into a neuroprotective and regenerative M2 phenotype will have important consequences for neuroimmune interactions and neuronal outcome under inflammatory and/or neurodegenerative conditions.

Highlights

Aging is the leading risk factor for the development Parkinson’s disease (PD), a most prevalent central nervous system (CNS) movement disorder characterized by the progressive and selective degeneration of midbrain dopaminergic neurons of the substantia nigra pars compacta (SNpc) and their terminals in the striatum, the presence of intracellular aggregated inclusions containing α-synuclein (α-Syn), called Lewy bodies (LB), and an abnormal activation of the astroglial cell compartment (Hornykiewicz, 1993; Di Monte and Langston, 1995; Langston et al, 1998, 1999; Table 1).The chronic decrease of dopamine storage in the striatum is responsible for the gradual impairment of motor function leading to the classical motor features of PD, which include bradykinesia, rest tremor, rigidity and postural instability
In this work we have highlighted the evidences documenting a major role of gene-environment interactions directing the polarization of microglia toward an harmful M1 phenotype, that may predispose the brain to reach a critical threshold of inflammation, triggering a self-perpetuating cycle of inflammation and neuronal death
We pinpointed the role of Wingless-type MMTV integration site (Wnt) signaling in each of the steps involved in both the neuroprotective/destructive glial-mediated neuronal outcome in PD

Summary

INTRODUCTION

Aging is the leading risk factor for the development Parkinson’s disease (PD), a most prevalent central nervous system (CNS) movement disorder characterized by the progressive and selective degeneration of midbrain dopaminergic neurons (mDA) of the substantia nigra pars compacta (SNpc) and their terminals in the striatum, the presence of intracellular aggregated inclusions containing α-synuclein (α-Syn), called Lewy bodies (LB), and an abnormal activation of the astroglial cell compartment (Hornykiewicz, 1993; Di Monte and Langston, 1995; Langston et al, 1998, 1999; Table 1). A number of genetic mutations interact with certain risk factors, such as exposure to neurotoxins or endotoxins, resulting in a further exacerbation of glial activation In this condition, gene-environment interactions may drive a vicious cycle of oxidative stress and inflammation, contributing to the chronic PD progression (Di Monte et al, 2002; Marchetti and Abbracchio, 2005; Zhang et al, 2005; Whitton, 2007, 2010; Gao and Hong, 2008, 2011; Przedborski, 2010; Tansey and Goldberg, 2010; Gao et al, 2011, 2012; Lastres-Becker et al, 2012; Table 1)

Protective factors

Expression levels

Findings

CONCLUDING REMARKS AND FUTURE PERSPECTIVES