CFR Researchers Propose New Mechanism for Neurodegeneration in FTD
CFR Researcher Dr. Aimee Kao and team recently reported a novel role for progranulin that may help explain the profound neuronal loss that occurs in FTD. Working in the model organism C. elegans, a small roundworm highly amenable to microscopy and genetic study, Dr. Kao discovered that cells of worms lacking progranulin die differently than cells containing progranulin. Specifically, dying progranulin-deficient cells are cleared faster than cells containing progranulin. She went on to reproduce this finding in cultured mammalian cells in collaboration with CFR Researcher Dr. Bob Farese and team. Using macrophages isolated from progranulin knock out mice, they showed that macrophages lacking progranulin also engulfed dying cells faster than wild type cells.
Based on these findings, Dr. Kao and colleagues propose that the altered kinetics of cell clearance may be relevant to the development of FTD in patients with mutations in progranulin. “Progranulin’s involvement in the kinetics of apoptotic cell engulfment would have been challenging to observe in any other model organism,” Kao said, “but we can take what we learn in worms and apply it to other organisms.” She and her team hypothesize injured cells that might otherwise recover are instead destroyed in patients with progranulin mutations because of the faster clearance, ultimately leading to significant neuronal death and brain atrophy.
Dr. Kao’s work, published in the Proceedings of the National Academy of Sciences, has direct therapeutic implications. She notes, “If our model holds up, we will have identified a whole new set of molecules that can be used as targets in the treatment and prevention of FTD.”