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%. Additionally, I discovered that Progranulin inhibits PLA2G15, explaining why the loss
of Progranulin leads to neuropathology.

To validate my theory, I will combine my expertise in biochemistry, cell biology and multi-omics to
investigate two key aspects: the interaction dynamics between Progranulin and PLA2G15, whether Progranulin
acts as a protective shield for BMP, and if such an protection is critical for neuronal health.

In summary, 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.