Loss-of-function mutations in GRN cause frontotemporal dementia (FTD) with 
transactive response DNA-binding protein of 43 kD (TDP-43)-positive inclusions 
and neuronal ceroid lipofuscinosis (NCL). There are no disease-modifying 
therapies for either FTD or NCL, in part because of a poor understanding of how 
mutations in genes such as GRN contribute to disease pathogenesis and 
neurodegeneration. By studying mice lacking progranulin (PGRN), the protein 
encoded by GRN, we discovered multiple lines of evidence that PGRN deficiency 
results in impairment of autophagy, a key cellular degradation pathway. 
PGRN-deficient mice are sensitive to Listeria monocytogenes because of deficits 
in xenophagy, a specialized form of autophagy that mediates clearance of 
intracellular pathogens. Cells lacking PGRN display reduced autophagic flux, and 
pathological forms of TDP-43 typically cleared by autophagy accumulate more 
rapidly in PGRN-deficient neurons. Our findings implicate autophagy as a novel 
therapeutic target for GRN-associated NCL and FTD and highlight the emerging 
theme of defective autophagy in the broader FTD/amyotrophic lateral sclerosis 
spectrum of neurodegenerative disease.