Grant: CIHR Fellowship

We have recently identified IRF2BPL as a novel human disease gene causing a progressive and severe neurodegenerative disorder. Patients are born normal, but at age ~3-5 years, begin falling, develop seizures and eventually become immobile before the age of 10. Brain imaging in older patients shows progressive brain atrophy. Neuronal loss of IRF2BPL in fruit flies results in gradual neurodegeneration and behavioral defects reminiscent of the human condition. The function of IRF2BPL is very poorly understood across species. My preliminary data indicates that IRF2BPL can inhibit WNT signaling in vivo, a critical biological pathway conserved in animals with well-established roles in development including the brain. However, a role for WNT signaling in the mature brain and neurodegenerative disorders is currently ill defined. A cell based study suggested that IRF2BPL reduces WNT signaling activity by ubiquitinating beta-catenin, a core WNT activator. I hypothesize that IRF2BPL inhibits WNT signaling and that loss of IRF2BPL should result in excess WNT signaling in the postnatal brain. In this proposal, I will: 1) Determine the functional consequences of increased WNT signaling in mature brains and determine if IRF2BPL loss of function ectopically activates WNT signaling in vivo. 2) Determine if IRF2BPL targets beta-catenin or other proteins implicated in WNT signaling in flies, mice and human cells. 3) Generate and characterize Irf2bpl knockout mice and assess if WNT signaling is affected. I will also use these mice to model the human disease as they may serve as a therapeutic testing platform. Mechanistic insight into a role for WNT, which is highly therapeutically targetable as drugs have been developed to reduce WNT signaling, and IRF2BPL in the postnatal brain will deepen our understanding of both neurodevelopmental and neurodegenerative disorders.