Genetic mutations in Granulin (GRN) that result in reduced levels of its encoded protein, progranulin (PGRN), have been implicated in several distinct neurological disorders, depending on the degree of PGRN reduction. More specifically, haploinsufficiency resulting from heterozygous GRN mutations has been identified to be causal for a subset of patients with frontotemporal lobar degeneration (FTLD), an adult-onset neurodegenerative disease. Furthermore, homozygous loss-of-function GRN mutations result in neuronal ceroid lipofuscinosis (NCL), and single nucleotide variants that decrease plasma and brain PGRN levels are risk factors for Alzheimer’s Disease (AD). The clear association between reduced levels of PGRN and neurological disorders highlights the importance of adequate PGRN dosage in normal nervous system function. The overarching goal of this project is to better understand the precise cellular and molecular mechanisms that are involved in the regulation of PGRN. In order to reach this goal, we began by identifying factors that could potentially modulate phenotypes associated with PGRN haploinsufficiency. The preliminary data presented in this application clearly show that Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, is involved in the regulation of PGRN levels and can modulate phenotypes associated with PGRN reduction in vivo through microglia. To investigate this idea further, we propose the following three specific aims. In Specific Aim 1, we will determine whether altering Nlk levels specifically in microglia can modulate FTLD-related phenotypes in vivo using mouse genetics. Specifically, (1) we will first test whether constitutive loss of Nlk in microglia is able to induce FTLD-related neuropathological and behavioral phenotypes. (2) Conversely, we will examine if constitutive overexpression of Nlk in microglia can prevent or ameliorate these same phenotypes. We will focus on neuropathological changes and behavioral deficits that have been previously ascribed to PGRN reduction in FTLD-PGRN patients and Grn knockout mice. In Specific Aim 2, we will elucidate the molecular mechanism through which Nlk regulates Pgrn levels in microglia. We will (1) employ mouse genetics and isogenic human induced pluripotent stem cell-derived microglia to determine the receptor involved in Nlk-mediated regulation of Pgrn endocytosis and (2) utilize unbiased proteomics approaches to identify direct molecular targets of Nlk that function in this regulation. In Specific Aim 3, we will determine whether GRN-associated neuropathology can be suppressed or reversed by increasing Nlk expression in adulthood. ...