The Molecular Basis of Wnt/β-Catenin Signaling Pathways in Neurodegenerative Diseases

Abstract

Defective Wnt signaling is found to be associated with various neurodegenerative diseases. In the canonical pathway, the Frizzled receptor (Fzd) and the lipoprotein receptor-related proteins 5/6 (LRP5/LRP6) create a seven-pass transmembrane receptor complex to which the Wnt ligands bind. This interaction causes the tumor suppressor adenomatous polyposis coli gene product (APC), casein kinase 1 (CK1), and GSK-3β (glycogen synthase kinase-3 beta) to be recruited by the scaffold protein Dishevelled (Dvl), which in turn deactivates the β-catenin destruction complex. This inactivation stops the destruction complex from phosphorylating β-catenin. As a result, β-catenin first builds up in the cytoplasm and then migrates into the nucleus, where it binds to the Lef/Tcf transcription factor to activate the transcription of more than 50 Wnt target genes, including those involved in cell growth, survival, differentiation, neurogenesis, and inflammation. The treatments that are currently available for neurodegenerative illnesses are most commonly not curative in nature but are only symptomatic. According to all available research, restoring Wnt/β-catenin signaling in the brains of patients with neurodegenerative disorders, particularly Alzheimer’s and Parkinson’s disease, would improve the condition of several patients with neurological disorders. The importance of Wnt activators and modulators in patients with such illnesses is to mainly restore rather than overstimulate the Wnt/β-catenin signaling, thereby reestablishing the equilibrium between Wnt-OFF and Wnt-ON states. In this review, we have tried to summarize the significance of the Wnt canonical pathway in the pathophysiology of certain neurodegenerative diseases, such as Alzheimer’s disease, cerebral ischemia, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and other similar diseases, and as to how can it be restored in these patients.