Wnt/β-Catenin Signaling as a Point of Intervention to Spur Greater Neural Regeneration

Wnt signaling is a complicated but well studied portion of the regulatory systems governing regeneration. Numerous groups are engaged in the commercial development of regenerative therapies that are based on manipulation of this part of mammalian biochemistry. Of the more prominent ventures, Samumed has reached phase 3 trials with treatments of this type. This open access paper walks through the evidence for Wnt signaling to be a useful point of intervention for researchers aiming to increase neurogenesis and regenerative capacity in the aging brain. This will be developed as a means of treating neurodegenerative conditions, but success would lead to treatments beneficial for all older individuals.

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 substantia nigra pars compacta 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.

Link: https://doi.org/10.1111/acel.13101

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