Excess Wnt in neurological disease

Abstract

Wnt pathways are critical developmental signaling cascades that are conserved across multicellular life. A clear role for Wnt signaling in proper neural development has been well-established, yet less is known about its sustained expression and signaling in the mature nervous system. The precise role for Wnt pathways, canonical or otherwise, and individual Wnt components (ligands, receptors, transducers, effectors, and regulators) in the mature brain are poorly understood. However, genetic evidence implicating Wnt-related components in both neurodevelopmental and neurodegenerative disorders suggests that fine-tuned regulation of Wnt signaling is required for proper nervous system development and long-term homeostasis. Much has been documented about down-regulated Wnt signaling and its association with neurological conditions. Hence, the focus of this review is to consolidate and highlight the evidence for up-regulated Wnt transcription and/or signaling in neurodevelopmental and neurodegenerative disorders with a brief discussion on the role of deregulated Wnt in cancer. Finally, we touch upon the therapeutic prospect of Wnt inhibition in the nervous system.

Keywords: Wnt proteins; beta-catenin; neurodegeneration; neurodevelopment; neurodevelopmental disorders; neurological disorders.

Figure 1. Wnt signaling pathways.

In the β-catenin-dependent pathway, Wnt is considered ‘off’ when Wnt is not bound to FZD receptors and LRP5/6 co-receptors. β-catenin associates with the destruction complex (APC, Axin, CK1, GSK33), where it is phosphorylated by GSK-3 and CK1, followed by subsequent degradation via the proteasome. Wnt is considered ‘on’ when a Wnt ligand binds to LRP5/6 and FZD receptors, and the scaffold protein Dvl recruits Axin along with the kinases CK1 and GSK-3 to the membrane. This disrupts the formation of the destruction complex, preventing the phosphorylation and degradation of β-catenin. As a result, β-catenin accumulates in the cytoplasm and then translocates to the nucleus, where it activates transcription of Wnt target genes. In the Wnt/PCP pathway, small G proteins RhoA and RAC are activated via Dvl, resulting in signaling via the ROCK and Jnk signaling pathways. In the Wnt/Ca²⁺ signaling pathway, signaling is via heterotrimeric G proteins that activate PLC, which leads to a rise in intracellular Ca²⁺. This leads to the activation of calcineurin (Ca), calcium/calmodulin-dependent kinase II (CamKII), and PKC. Both CamKII and PKC activate various regulatory proteins such as NF-κB and CREB, and Cn can activate the cytoplasmic protein NFAT. CamKII, calcium/calmodulin-dependent kinase II; Wnt, wingless/integrated.

Figure 2. Wnt in ASD.

Manually curated association of 59/102 top ASD genes and 16 negative regulators with known roles in Wnt/β-catenin signaling. ASD, Autism spectrum disorders; Wnt, wingless/integrated.