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.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…The authors showed a significant increase in the SVZ-derived NSCs of the third ventricle (3V) and Aq-surrounding regions. Hence, the SN newborn DAergic neurons were mainly derived from the migration and differentiation of the NSCs in the SVZ of 3V-and Aq-adjacent regions (Xie et al, 2017), thus supporting our indication that quiescent neuroprogenitors of mNSCs can be activated not only in vitro (L'Episcopo et al, 2011c), but more importantly, in vivo, upon SNpc-DAergic lesions with PD neurotoxins (L'Episcopo et al, 2014b).After our first studies demonstrating dysregulated WβCsignalling in the MPTP mouse model of PD, both in vivo and in vitro(L'Episcopo et al, 2011a;b), more recent reports corroborated the key role of WβC in the physiopathology of PD (seeMarchetti, 2018…”

“…After our first studies demonstrating dysregulated WβC‐signalling in the MPTP mouse model of PD, both in vivo and in vitro (L'Episcopo et al, ;b), more recent reports corroborated the key role of WβC in the physiopathology of PD (see Marchetti, for an up‐to‐date review). Among others, Singh, Mishra, Bharti, et al () used short hairpin (sh)RNA‐lentiviruses to genetically knockdown AXIN2 to up‐regulate WβC‐signalling in the SNpc, in 6‐OHDA‐induced parkinsonism rats.…”

“…In the last decade, we have explored the functional role of adult neurogenesis in PD by addressing the molecular and cellular NSC regulatory mechanisms underlying the age‐dependent decline of neurogenic potential in a 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine/1‐methyl‐4‐phenylpyridinium (MPTP/MPP + )‐induced rodent model of basal ganglia injury, investigating the potential to stimulate adult neurogenesis as a means to support neuroprotective and neurorestorative therapies (L'Episcopo, Serapide, et al, ; L'Episcopo et al, , , , ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti, ; Marchetti et al, ; Marchetti & Pluchino, ). Particularly, we concentrated on the key pathway regulating DAergic neurogenesis, from neurodevelopment through aging and neurodegeneration: the wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling cascade (Brodski, Blaess, Partanen, & Prakash, ; Inestrosa & Arenas, ; Maiese, ; Maiese, Faqi, Chong, & Shang, ; Marchetti, ; Nusse & Clevers, ; Nusse & Varmus, ; Palomer et al, ; Salinas, ; Tapia‐Rojas & Inestrosa, ; Toledo et al, ; Wurst & Prakash, ). The WβC‐signalling pathway is of utmost importance owing to its ability to promote tissue repair and regeneration of stem cell activity in diverse organs, and in light of its crucial role in age‐related pathogenesis and therapy of disease (Banerjee, Jothimani, Prasad, Marotta, & Pathak, ; Garcìa, Udeh, Kalahasty, & Hackam, ; Garcìa‐Velasquez & Arias, ; Nusse & Clevers, ; Tauc & Jasper, ; Toledo et al, ).…”

“…The mechanisms underlying these phenomena constitute a synergy between (a) the upregulation of proinflammatory glial pathways, (b) the decline of anti‐oxidant self‐defence mechanisms, such as the nuclear factor erythroid‐2‐related factor 2 (Nrf2) ‐heme oxygenase 1 (Hmox1) axis, a key mediator of cellular adaptive response, and (c) the decline of astrocyte‐derived Wnts leading to NSC neurogenic impairment, with a consequent failure to recover from a PD insult. As a result, both pharmacological and cellular therapies involving the up‐regulation of WβC‐signalling and immunomodulation were reported to ameliorate the aged microenvironment, thereby promoting endogenous neurogenesis, ultimately boosting a full neurorestoration program in the aged PD brain (L'Episcopo et al, , , ; L'Episcopo et al, ; L'Episcopo, Tirolo, Serapide, et al, ; Marchetti, ; Marchetti et al, ; Marchetti & Pluchino, ). While little is known on WβC ‐ signalling in the PD‐injured hippocampus, it seems plausible that a comparable dysfunction of the WβC ‐ pathway may well be at play in the SGZ of the DG, with potential consequences for hippocampal neurogenesis in PD and its involvement in non‐motor symptoms of PD.…”

“…The therapeutic relevance of endogenous neurogenesis for the recovery of the injured brain and, particularly, the aged PD brain, is being actively investigated, yet remains to be elucidated (van den Barker et al, 2018;Kempermann et al, 2018;Le Grand, Gonzalez-the up-regulation of WβC-signalling and immunomodulation were reported to ameliorate the aged microenvironment, thereby promoting endogenous neurogenesis, ultimately boosting a full neurorestoration program in the aged PD brain (L'Episcopo et al, 2011c(L'Episcopo et al, , 2012L'Episcopo et al, 2014a;L'Episcopo, Tirolo, Serapide, et al, 2018aMarchetti, 2018;. While little is known on WβC-signalling in the PDinjured hippocampus, it seems plausible that a comparable dysfunction of the WβC-pathway may well be at play in the SGZ of the DG, with potential consequences for hippocampal neurogenesis in PD and its involvement in non-motor symptoms of PD.…”