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

Abstract

A common hallmark of age‐dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC ‐signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct‐periventricular region (Aq‐PVR) Wnt‐sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β‐catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial‐derived factors regulating WβC‐dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in “turning off” the WβC neurogenic switch via down‐regulation of the nuclear factor erythroid‐2‐related factor 2/Wnt‐regulated signalosome, a key player in the maintenance of antioxidant self‐defense mechanisms and NSC homeostasis. Harnessing WβC‐signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.

Abstract

Harnessing WβC signalling activation in the aged, inflamed PD brain. A “Wnt‐on” neurorestoration program instructed by grafted NSCs and a panel of pharmacological treatments rescuing the impaired neurogenic niches is illustrated. With age, the inflamed microenvironment coupled to dysfunctional astrocyte–microglia interactions and environmental toxin exposure (MPTP) inhibit active Wnt signalling (“Wnt‐off” condition), leading to exacerbation of inflammation and inhibition of Wnt‐dependent proregenerative/self‐repair potential, with harmful consequences for SVZ and Aq‐PVR niches, mDA neuron survival and repair from MPTP injury. The ability of NSC grafts, NSC‐derived astrocytes and endogenous astrocytes to switch the inflammatory/Wnt‐genetic cascade via astrocyte–neuron and astrocyte–microglia crosstalk both at the SNpc and at the Aq‐PVR DA niche levels is illustrated. Reciprocally, astrocyte‐derived Wnt1 further influences both exogenous and endogenous NSCs and reduces microglia pro‐inflammatory status, thus favouring beneficial effects for an overall TH neurorescue (“Wnt on”) program.