Intracellular signaling pathways initiated by the growth factor Wnt play a number of important roles during embryonic development, and have more recently been linked to the function of synapses in the adult brain1. Wnt signaling is involved in the assembly of both the pre- and postsynaptic neuronal compartments as well as synaptic plasticity and maintenance. The Wnt inhibitor Dickkopf-1 (Dkk1) causes a dispersion of synaptic proteins that results in disassembly2.
With 19 genes encoding Wnt proteins and at least 15 different receptors and co-receptors identified to date, Wnt signaling is extremely complex. Extracellular Wnt binds to transmembrane cell surface receptors in the frizzled (Fz) and low-density lipoprotein-related protein (LRP) families. Activation of these receptors induces a hyperphosphorylation of Dishevelled (Dsh) proteins, resulting is one of three downstream signaling cascades: a “canonical” pathway that affects gene transcription through β-catenin, or two noncanonical, β-catenin-independent pathways that regulate the cytoskeleton and intracellular calcium levels1.
Synapse loss has emerged as an early pathological hallmark of the neurodegenerative disorder Alzheimer’s disease (AD) and is associated with cognitive decline in the illness3. The soluble form of amyloid-β (Aβ) may be to blame for this synapse loss, perhaps through a disruption of Wnt signaling2, 4. For example, the binding of soluble Aβ to Fz5 blocks Wnt signaling in vitro, and levels of Dkk1 are elevated in AD brains3, 5.
In addition to AD, Wnt signaling may have a hand in many other diseases of synaptic dysfunction, including Parkinson’s disease, schizophrenia, and autism. The knowledge that perturbation of Wnt signaling disrupts the integrity of synapses suggests that this pathway may be a therapeutic target for AD and other synaptic diseases6.
Below is the current listing of Bethyl antibodies involved in Wnt signaling pathway research: