The role of the frontotemporal dementia gene product Progranulin in the homeostasis of the neurodegeneration- associated lipid Bis(monoacylglycero)phosphate

The brain relies on Progranulin, a pivotal protein, to function smoothly and maintain overall health. When Progranulin fails to perform its essential functions, it can trigger severe neurological issues. In children, a complete malfunction of Progranulin can result in Batten disease, a devastating condition characterized by rapid neurological decline. In adults, even partial dysfunction can lead to debilitating disorders such as frontotemporal dementia and significantly increase the risk of developing Parkinson’s disease.

Diving deeper into Progranulin's role, it turned out to be vital for the functionality of lysosomes, the cell's waste disposal units responsible for recycling cellular debris. Proper lysosomal function requires sufficient levels of a specific lipid molecule called Bis(monoacylglycero)phosphate (BMP). When Progranulin is deficient, BMP levels drop, leading to detrimental effects on neuronal health. I recently identified PLA2G15 as the enzyme responsible for degrading BMP. Inhibition of PLA2G15 dramatically increases BMP levels in cells and mouse models. This increase is significant, as inhibiting PLA2G15 reduced neuropathology in a Niemann-Pick disease mouse model—an extremely severe early-onset neurodegenerative disease—and improved the lifespan of these mice by an impressive 60%.

My goal is to unravel Progranulin's critical role in brain health, with the hope that our discoveries can pave the way toward boosting BMP as an effective therapeutic strategy for various neurodegenerative diseases.