It has been more than a decade since heterozygous loss-of-function mutations in 
the progranulin gene (GRN) were first identified as an important genetic cause 
of frontotemporal lobar degeneration (FTLD). Due to the highly diverse 
biological functions of the progranulin (PGRN) protein, encoded by GRN, multiple 
possible disease mechanisms have been proposed. Early work focused on the 
neurotrophic properties of PGRN and its role in the inflammatory response. 
However, since the discovery of homozygous GRN mutations in patients with a 
lysosomal storage disorder, investigation into the possible roles of PGRN and 
its proteolytic cleavage products granulins, in lysosomal function and 
dysfunction, has taken center stage. In this chapter, we summarize the GRN 
mutational spectrum and its associated phenotypes followed by an in-depth 
discussion on the possible disease mechanisms implicated in FTLD-GRN. We 
conclude with key outstanding questions which urgently require answers to ensure 
safe and successful therapy development for GRN mutation carriers.