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.

Bianca Marchetti

doi:10.3390/ijms19123743

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.

Highlights

Parkinson’s disease (PD) is the most common movement disorder, and the second most common aging-related neurodegenerative disease after Alzheimer’s disease
Neuroinflammation appeared to play unsuspected roles, since Wnt1/β-catenin signaling and MPTP-reactive astrocyte cross-talk with both mDAergic neurons and microglial cells were unveiled as candidate components of the neurorescue pathways involved in nigrostriatal DAergic plasticity and in the regulation of evolutionarily conserved Wnt/β-catenin pathway initiates a signaling cascade that is crucial during both normal embryonic development and throughout the life of the organism in almost every tissue and organ system
Between 3 and 14 dpt, a significant decline of active glycogen synthase kinase 3β (GSK-3β) levels was measured, when ameboid IBA1+ microglial cells in striatum and subtantia nigra pars compacta (SNpc) were significantly reduced. These findings indicated that MPTP induced Fzd1/β-catenin downregulation and GSK-3β activation within the temporal window of active DAergic degeneration and microglial activation, whereas the recovery of canonical Wnt/β-catenin was associated with the gradual DAergic self-repair phase and downmodulation of microglial activation [49]

Summary

Introduction

Parkinson’s disease (PD) is the most common movement disorder, and the second most common aging-related neurodegenerative disease after Alzheimer’s disease. Neuroinflammation appeared to play unsuspected roles, since Wnt1/β-catenin signaling and MPTP-reactive astrocyte cross-talk with both mDAergic neurons and microglial cells were unveiled as candidate components of the neurorescue pathways involved in nigrostriatal DAergic plasticity and in the regulation of evolutionarily conserved Wnt/β-catenin pathway initiates a signaling cascade that is crucial during both normal embryonic development and throughout the life of the organism in almost every tissue and organ system.

Results

Conclusion