Elisa Arthofer: The Fascination of “Frizzled” Receptors, G-proteins, and Human Health
Her work is especially exciting because of its potential to help patients with Norrie disease – an inherited eye disorder that causes blindness in infant boys due to impaired blood supply to the retina and other body systems. Patients with another hereditary disorder, familial exudative vitreoretinopathy, may also benefit from her work. This disease affects both sexes and interferes with blood vessel formation at the edges of the retina, causing retinal damage and vision loss.
The common factor in both diseases is a class of receptors called “Frizzleds” (FZDs), originally named for the abnormal orientation of hairs in fruit flies with a fz gene mutation (picture a fruit fly with a bad-hair day). FZD receptors occur in cells throughout the animal kingdom, and are located in the cell membrane – crossing it seven times in a serpentine pattern. Binding to a messenger molecule at the external cell surface alters the shape of the FZD receptor facing into the cell. This altered FZD conformation can then interact with intracellular “G proteins” that initiate signaling within the cell. As Arthofer puts it: “G proteins are a special group of proteins with tremendous importance, holding many physiological roles such as the formation of blood vessels in our entire organism.” Nearly half of all drugs act via G-protein-linked receptors!
Arthofer’s work focuses on FZD4, one of 10 types of FZD receptors involved in the large Wnt signaling pathway, a highly conserved pathway (i.e., little change over long time periods and many species). Many signaling pathways begin with Wnt molecules binding to compatible FZD receptors. Because FZD4 specifically affects human vascularization, especially in the brain and retina, a FZD4 mutation that impairs this important ligand-receptor binding can cause the diseases above. Arthofer was the first to “dissect distinct signaling mechanistics underlying the molecular interactions of a specific WNT ligand, a FZD4 receptor, and the respective G protein.” Her group was also the first to demonstrate a mechanistic and functional interaction of a FZD receptor and a specific class of G proteins in mammals. This class was already known to play a role in vascular development, but hadn’t previously “been linked to a member of the FZD family.” The findings appear to hold significant clinical relevance.
“The only successful way to change and … improve receptor-targeted drug discovery is by aiming at understanding the underlying molecular mechanisms,” says Arthofer, who feels that mechanism-focused drug discovery and development will reduce the failure rate of drug candidates in clinical trials, save precious time for patients, and save large amounts of money.
Besides, “there is just something so fascinating about the fact that I, as a human, look at a dish of cells … trying to manipulate [them] in order to understand how life works and ultimately how we can better understand our bodies … especially when we are sick! Doesn’t that sound really amazing and fascinating at the same time?”
The preceding article is part of a series featuring the scientific work of 20 young Austrian researchers, all who are active members of the OSTA's Research and Innovation Network Austria. The initial presentation of their work took place at the ASCINA poster session under the auspices of the "Austrian Research and Innovation Talk" in Toronto on October 21, 2016. Three of these scientists were subsequently awarded the ASCINA award the same evening, honoring their outstanding scientific work.