Wnt/β-Catenin Signaling Pathway Governs a Full Program for Dopaminergic Neuron Survival, Neurorescue and Regeneration in the MPTP Mouse Model of Parkinson's Disease

Abstract

Wingless-type mouse mammary tumor virus (MMTV) integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation to axonal extension, synapse formation, neurogenesis, and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional β-catenin protein which is a potent co-activator of transcription factors such as lymphoid enhancer factor (LEF) and T-cell factor (TCF). Accumulating evidence points to dysregulation of Wnt/β-catenin signaling in major neurodegenerative disorders. This review highlights a Wnt/β-catenin/glial connection in Parkinson's disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. Major findings of the last decade document that Wnt/β-catenin signaling in partnership with glial cells is critically involved in each step and at every level in the regulation of nigrostriatal DAergic neuronal health, protection, and regeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, focusing on Wnt/β-catenin signaling to boost a full neurorestorative program in PD.

Keywords: Parkinson’s disease; Wnt/β-catenin signaling; cell death; dopaminergic neurons; glia–neuron cross-talk; neurodegeneration; neuroprotection; neurorepair.

Figure 1

Schematic representation of canonical Wingless-type mouse mammary tumor virus (MMTV) integration site (Wnt) pathway and non-canonical Wnt/Ca²⁺ and Wnt/planar cell polarity (PCP) pathways [38,39,40,41,42,43]. (A) In the Wnt off state (i.e., in the absence of a Wnt ligand), cytoplasmic β-catenin is constantly degraded by the action of the Axin complex. Casein kinase 1 (CK1) and glycogen synthase kinase 3β (GSK-3β) sequentially phosphorylate the amino terminal region of β-catenin, resulting in β-catenin ubiquitination and proteasomal degradation (red box). In the Wnt on state, canonical Wnt/β-catenin pathway activation starts with Wnt binding Frizzled (Fzd) receptor and the co-receptor low-density lipoprotein receptor-related protein 5/6 (LRP5/6), which induces the recruitment of Dishevelled (Dvl) leading to the inhibition of the β-catenin destruction complex formed by Axin, adenomatous polyposis coli (APC), GSK-3β, and CK1. This inhibition causes the accumulation of β-catenin, which is no longer phosphorylated by the destruction complex. β-catenin then translocates to the nucleus where it activates transcription of Wnt target genes. (B) In the non-canonical Wnt/Ca²⁺ pathway, the binding of Wnt to Fzd activates the heterotrimeric G-proteins. These signal through phospholipase C (PLC) and inositol 1,4,5-triphosphate (IP3) to induce the release of intracellular Ca²⁺ and the activation of protein kinase C (PKC) and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Multiple interactions are possible between the targets of the Wnt/Ca²⁺ and the canonical Wnt/β-catenin pathway at different points. Additionally, Kny, Ror2, or Ryk receptors with Fzd receptors can activate c-Jun N-terminal kinase (JNK), promoting target gene expression through activator protein 1 (AP-1). In non-canonical Wnt/PCP pathway, Wnt proteins bind to Fzd, which activates small guanosine triphosphatases (GTPases) proteins Rho and Rac and c-Jun N-terminal kinase via Dvl. This interaction results in cytoskeletal regulation and involves polarized cell shape changes and cytoskeleton rearrangement.

Figure 2

Schematic illustration of Wnt1/β-catenin signaling regulation of midbrain dopaminergic (mDAergic) neuron survival/death according to our published findings [49,50,51,52,53,54,55,56,57]. Major environmental factors including aging, inflammation, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure may increase oxidative load and a panel of endogeneous Wnt antagonists (Dickkopf1 (Dkk1), Wnt inhibitory factor (WIF), frizzled-related proteins (sFRPs)) that, in synergy with genetic mutations and dysfunctional glia–neuron interactions, antagonize canonical Wnt/β-catenin signalling (“Wnt off”) in mDA neurons. Upregulation of active GSK-3β then leads to β-catenin degradation promoting DA neuron death. In the presence of canonical Wnt1-like agonists (such as R-spondin (Rspo) or Norrin), GSK-3β antagonists, or nitric oxide non-steroidal anti-inflammatory drug (NO-NSAID) treatments, activation of Wnt/β-catenin (“Wnt on”) contributes to maintaining the integrity of mDA neurons via blockade of GSK-3β-induced phosphorylation and proteasomal degradation of the neuronal pool of β-catenin. β-catenin then translocates into the nucleus and associates with a family of transcription factors regulating the expression of Wnt target genes involved in mDAergic neuron survival. Schematic drawing based on published results on Wnt signaling in PD [49,50,51,52,53,54,55,56,57].

Figure 3

Schematic illustration of Wnt1/β-catenin signaling as a key player in glia–neuron cross-talk. A simplified scheme linking reactive astrocytes, mcroglia, and Wnt/β-catenin signaling to mDAergic neuron survival/death is summarized according to our published findings [49,50,51,52,53,54,55,56,57]. Upon injury, a number of conditons, including astrocyte activation, the genetic and hormonal background (i.e., gender and estrogens), and endogenous and exogenous activators of Wnt/β-catenin signaling components (i.e., GSK-3β-antagonists), can promote astrocyte beneficial effects via the expression of a panel of growth/neurotrophic factors, particularly Wnt1, contributing to the survival, repair, and neurorescue of DA neurons, via direct neuronal effects (see Figure 2) and through the inhibition of the microglia-M1 activated phenotype. Astrocytes of the ventral midbrain, via activation of Wnt/β-catenin signaling, can also promote neurogenesis and DAergic neurogenesis from adult neural stem/progenitor cells. By contrast, aging, MPTP exposure, and genetic mutations exacerbate microglia activation, with upregulation of a wide panel of pro-inflammatory mediators including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), Wnt5a, inducible nitric oxide synthase (iNOS-derived) nitric oxide (NO) and reactive oxygen (ROS) and reactive nitrogen (RNS) species. Neurotoxic injury or increased oxidative load as a result of gene–environment interactions may antagonize Wnt/β-catenin signaling in DA neurons by upregulating active GSK-3β, leading to β-catenin degradation and increased DA neuron vulnerability.