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By Michalina Hanzel, PhD
The multifaceted roles of the Wnt family of glycoproteins have been extensively characterized throughout embryonic development and adult homeostasis. The highly conserved, cell- and tissue- specific proteins orchestrate processes ranging from neural induction, cell proliferation and migration to adult neurogenesis and neuronal maintenance and regeneration. Recently, Wnt proteins have been proposed to have key roles in regulating pathological processes in the brain, especially those observed in neurodegenerative disorders, often resulting from pathological states of neuroinflammation.
The Wnt signaling pathway is involved in embryogenesis and is implicated in different cancers. The canonical pathway involves a signaling cascade including the Frizzled and Dishevelled protein families and beta-Catenin which ultimately inhibits AXIN, GSK-3, and APC. Non-canonical Wnt pathways are involved in regulation of the cytoskeleton and intracellular calcium levels and have been implicated in neurodegeneration.
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The Wnt landscape is complex and comprises three, largely independent yet interactive, signaling cascades. In the canonical Wnt signaling pathway, binding of a Wnt ligand to the Frizzled-LRP5/6 complex results in the stabilization and accumulation of hypophosphorylated beta-catenin that is able to translocate to the nucleus and, through binding to the TCF/LEF transcription factors, initiates transcription of a number of Wnt target genes. Once the pathway is inactivated, beta-catenin becomes phosphorylated by the beta-catenin destruction complex and is degraded by the proteasome. The non-canonical Wnt/PCP pathway also requires a Wnt ligand interaction with the Frizzled receptor, however, downstream activation of Dishevelled and RhoA, Rac and cdc42 leads instead to cell polarity and cytoskeletal rearrangements. Moreover, a non-canonical Wnt/Ca2+ pathway activation results in the release of calcium from intracellular stores. A complex inter-regulation is observed between the canonical and non-canonical pathways and many levels of regulation exist at different steps of the Wnt cascade. Due to all this complexity and the vast diversity of downstream signaling this basic classification of the pathways has become somewhat outdated and any future therapeutic interventions require a careful analysis of all context-dependent interactions.
The derailed brain neuroinflammatory response has surfaced in recent years as a critical element in the development and progression of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Controlling this immune inflammatory response is a fundamental goal in disease treatment and Wnt pathway components present likely candidates for developing therapeutics. The currently accepted view is that canonical Wnt signaling acts as an anti-inflammatory mechanism, whereas the non-canonical pathway’s activity is pro-inflammatory. However, the physiological and cellular context is vital when the outcome of Wnt pathway activation is considered. For example, a prototypical non-canonical pathway ligand, WNT-5A is associated with the maintenance of innate immune responses during normal homeostasis. However, expression of WNT-5A upregulates the production of proinflammatory cytokines in primary microglia, mediating their proinflammatory transformation. In Alzheimer’s disease, WNT-5A directed neuroinflammation contributes to neurotoxicity and neural degeneration, prompting research into Wnt modulatory therapeutics.
A recent study in an Alzheimer's disease mouse model has found that an inhibitor of the canonical Wnt signaling, Dickkopf-1 (Dkk-1), is induced by beta-amyloid and, in a positive feedback loop, promotes the non-canonical Wnt-PCP pathway, which progressively leads to synapse retraction and eventual neuronal loss. Importantly, the researchers found that antagonizing the Wnt-PCP pathway with a drug fasudil reduced the beta-amyloid-dependent synaptotoxicity by restoring the balance between the two Wnt pathways, in favor of the canonical pathway.
In the future, harnessing Wnt signaling for regulating inflammation in the central nervous system may emerge as one of the most powerful tools in the fight to control the immune homeostasis in health and disease.
Michalina Hanzel, PhD
Postdoctoral Associate at The Rockefeller University
Dr Hanzel is currently studying synaptic function in the cerebellum to understand neurodevelopmental disorders and has a background in developmental neurobiology, molecular and cell biology.
References
Sellers, Katherine J. et al. "Amyloid Β Synaptotoxicity Is Wnt-PCP Dependent and Blocked by Fasudil." Alzheimer's & Dementia 14.3 (2018): 306–317.
Zolezzi, Juan M., and Nibaldo C. Inestrosa. "Wnt/TLR Dialog in Neuroinflammation, Relevance in Alzheimer's Disease." Frontiers in Immunology 8 (2017): 187.Kumawat, Kuldeep, and Reinoud Gosens. "WNT-5A: Signaling and Functions in Health and Disease." Cellular and Molecular Life Sciences 73 (2016): 567–587.
Marchetti, Bianca, and Stefano Pluchino. "Wnt Your Brain Be Inflamed? Yes, It Wnt!" Trends in molecular medicine 19.3 (2013): 144–156.
