Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals younger than 65. Loss-of-function mutations in the progranulin (PGRN) gene have been shown to be one of the leading causes of FTLD. Mutations in PGRN lead to a neuropathology which is characterized of by the presence of ubiquitinated TAR-DNA binding protein (TDP-43) inclusions. A major unresolved question in the field is the exact relationship between PGRN and TDP-43. Clues to this relationship lie with the TDP-43 inclusions. The presence of ubiquitinated TDP-43 suggests a problem with TDP-43 degradation. We have shown that a major mode of TDP-43 degradation is through autophagy. We have obtained exciting preliminary data showing that basal autophagy induction is reduced in 6-month-old PGRN knockout mice. Additionally these changes correlate with a significant decrease of the ubiquitin binding protein p62, which serves as shuttling factor for select ubiquitinated proteins, such as TDP-43, towards autophagy degradation. Together these findings lead us to the following working hypothesis: Lack of progranulin leads to TDP-43 accumulation by (i) impairing autophagy induction and by (ii) lowering TDP-43 targeting to autophagic degradation via a p62- mediated mechanism. To test this hypothesis, we will use multidisciplinary approaches that will allow us to identify the mechanistic links between the lack of PGRN and TDP-43 accumulation. To elucidate the pathways linking PGRN and autophagy, we will use a lentiviral vector to increase ERK signaling to rescue autophagy in PGRN knockout mice. Further, we will measure autophagy induction in primary neurons and aged mice to investigate the role of PGRN in autophagy. We will investigate the role of p62 in TPD-43 accumulation. Primary neuronal cultures will be used to determine the signaling pathways leading to reduced p62 levels in PGRNko/ko mice and the molecular mechanisms by which reduction of p62 levels leads to TDP-43. We also will test the hypothesis that autophagy dysfunction facilitates TDP-43 accumulation. We will use a pharmacological approach to increase autophagy in transgenic mice expressing mutant TDP-43 that exhibit cognitive and motor deficits as well as TDP-43 accumulation. These experiments will test whether increasing autophagy may represent a possible therapeutic approach for the treatment of FTLD-TDP and will further elucidate the role of autophagy in TDP-43 pathogenesis. Successful completion of these proposed studies will represent a significant contribution to the field, and the data obtained has the potential to identify novel therapeutic targets in the fight against FTLD and TDP-43 proteinopathies. PUBLIC HEALTH RELEVANCE: Frontotemporal lobar degeneration is the second most common form of dementia in people younger than 65. Our studies are aimed at understanding the molecular and cellular mechanisms underlying the basis of cognitive decline. The results of the proposed experiments will facilitate the identification of potential therapeutic targets for ths insidious disorder.