Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) are two devastating neurodegenerative diseases with significant genetic, pathological, and clinical overlap. The hexanucleotide repeat expansion in the C9ORF72 gene is a leading cause of both diseases. Disease progression is contributed by both the loss of function of C9ORF72 protein and the gain of toxicity due to the accumulation of RNA and dipeptide repeats. However, the exact function of C9ORF72 remains to be elucidated. Here, I explored the cellular role of C9ORF72 utilizing C9ORF72 deficient cell lines and mice. C9ORF72 deficiency results in enhanced inflammatory responses, leading to splenomegaly and lymphadenopathy in mice. I show that several immune signaling pathways are upregulated under C9ORF72 deficient conditions, including the previously reported endosomal TLR signaling pathways, the cGAS-STING signaling pathway, and the JAK-STAT1 pathway. Furthermore, I show that inhibiting JAK1/2 activity rescues splenomegaly and lymphadenopathy in C9orf72-/- mice. Even though the exact mechanism that leads to the upregulation of the JAK-STAT1 pathway is unclear, I propose that compromised lysosome integrity under C9ORF72 deficient condition can induce inflammation in a JAK-STAT1 dependent manner. Altogether, my data identified a mechanism by which C9ORF72 regulates inflammation, which might facilitate therapeutic development for ALS/FTLD with C9ORF72 mutations. Another gene of interest is GRN, mutation of which is one of the main causes of FTLD and another fatal neurodegenerative disease termed neuronal ceroid lipofuscinosis (NCL). The exact pathological mechanisms of how the loss of progranulin (PGRN), the protein encoded by the GRN gene, contributes to the diseases remain unclear. To explore the role of PGRN, we identified Fibroblast Activation Protein (FAP) as a novel interactor of progranulin and studied the significance of this interaction. We also discovered that the levels of a lysosomal enzyme Palmitoyl-Protein Thioesterase 1 (PPT1) are reduced under progranulin-deficient conditions and studied the role of PPT1 in mediating lysosomal functions of PGRN. These studies expand our knowledge of the cellular pathways regulated by progranulin and provide future directions to study progranulin functions.