Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotection/repair in Parkinson's disease

Abstract

During the past three decades, the Wingless-type MMTV integration site (Wnt) signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson's disease (PD), a common neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic (mDA) neurons and deregulated activation of astrocytes and microglia. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/β-catenin signaling in mDA neurons and subventricular zone (SVZ) neuroprogenitors via astrocyte-microglial interactions. Dysregulation of the crosstalk between Wnt/β-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostriatal dopaminergic self-repair in PD. These findings hold a promise in developing therapies that target Wnt/β-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD.

Protective Effect of Curcumin Against Oxidative Stress-Induced Injury in Rats with Parkinson’s Disease Through the Wnt/ β-Catenin Signaling Pathway

“…Wnt signals are transduced by canonical and non-canonical pathways, relying on the expression profiles of Wnt ligands, coreceptors, the Fzd family receptors, Wnt antagonists, and the activity of cytoplasmic Wnt signaling regulators [18]. Evidence has shown that the Wnt/β-catenin signaling pathway is involved in PD pathogenesis [33]. In vivo and in vitro studies have revealed that Wnt3 is present in the hippocampal neurogenic niche and regulates newborn neurogenesis in the dentate gyrus [20].…”

Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

“…However, Wnt1 becomes expressed in reactive astrocytes upon injury of this region (reviewed in L'Episcopo et al . ). Thus, it is tempting to speculate that dopaminergic neurons within DA 1 (specifically subtype DA 1A ) are more vulnerable to toxic insults (and perhaps to the PD disease process) given that they do not express Fzd1.…”

HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/β-Catenin Signaling Pathway

“…In this family, BDNF appears to exhibit the most potent activity in neural development and neuroplasticity (Mitchelmore and Gede 2014; Nosheny et al 2005). BDNF has also been implicated in the etiology of diverse types of neurological disorders (Harte-Hargrove et al 2013), such as depression (Manosso et al 2015; Stuke et al 2012), schizophrenia (Notaras et al 2015; Reinhart et al 2015; Zhang et al 2016), Alzheimer’s disease (AD) (Phillips et al 1991; Tapia-Arancibia et al 2008), Huntington’s disease (HD) (Borrell-Pages et al 2006), and Parkinson’s disease (PD) (L’Episcopo et al 2014). Remarkably, many recent studies have shown that BDNF is emerging as a particularly important player in neuropathic pain (Coull et al 2005; Inoue 2009; Itokazu et al 2014).…”