The role of prograulin in mitochondrial function in frontotemporal dementia

GRN mutations which result in haploinsufficiency of progranulin cause frontotemporal dementia (FTD) with TDP-43 pathology. Reduced mitochondrial function and mitophagy, which is the clearance of damaged mitochondria, have been identified in several neurodegenerative diseases. A number of genes linked to FTD, such as VCP and TBK1, are known to play a role in mitophagy. However, whether progranulin is necessary for mitochondrial health has not yet been directly investigated.

This project will use a variety of biochemical and imaging techniques to examine if progranulin plays a role in mitophagy or mitochondrial function. We will use induced pluripotent stem cells (iPSCs) derived from patients with GRN mutations as well as wild-type and FLAG-Parkin overexpressing SHSY5Y cells where progranulin has been knocked down using small interfering RNA (siRNA). Mitochondrial health is particularly important in neurons as oxidative phosphorylation is their primary method for generating ATP. Examining whether progranulin is involved in mitochondrial function and mitophagy is important to understand how haploinsufficiency of progranulin can lead to FTD and may identify new therapeutic targets.