2015 Program Grant funded for $100,000
Mis-regulation of activity-dependent protein synthesis is one of the major cellular abnormalities found in fragile X. Upstream neuronal signaling regulates a large cluster of enzymes called the mTORC1 complex, which in turn regulates protein synthesis. This complex is also controlled by cellular energy levels via the metabolic sensor AMP-activated Protein Kinase (AMPK). AMPK is a highly conserved kinase that is activated under conditions of energy stress, when intracellular ATP levels decline and intracellular AMP increases. AMPK normally mediates mTORC1 suppression, but AMPK appears to be decreased in fragile X.
Metformin, an FDA-approved drug, is widely used as a first-line therapy for type 2, and is a well known activator of AMPK. It controls gene expression at the level of mRNA translation, comparable to the mTORC1 inhibitor rapamycin. This project will explore the potential of metformin and related compounds to rescue known abnormalities in fragile X knockout mice, and investigate its therapeutic potential. Side effects of metformin in patients are rare, even with chronic administration, so this is a potential off-the-shelf treatment for fragile X.