The Role of Sting in Lysosomal Storage Disorder

PROJECT SUMMARY Lysosomal storage disorder (LSD) is a collection of over 70 monogenic diseases associated with genetic mutations in lysosomal enzymes or proteins. The clinical manifestations of LSD are heterogenous but often include early-onset neurodegeneration with varying degrees of inflammation. The mechanism of inflammation associated with LSD is unknown. We recently showed in Niemann-Pick disease type C1 that an intracellular innate immune signaling pathway, STING, is activated due to impaired lysosomal degradation, leading to inflammation and neuropathology. In this R21 application, we aim to directly examine whether STING is required for pathogenesis of several lysosomal storage disorders using mouse models. We hypothesize that STING is an “immunosensor” of lysosome activity and that lysosomal dysfunction activates the STING- mediated immune signaling and lysosomal biogenesis. In Aim 1, we will breed mouse models of lysosomal storage disorder with Sting-/- mice or treat with a STING antagonist to determine whether STING is required for inflammation and disease pathogenesis. In Aim 2, we will elucidate the mechanisms of STING activation and STING-mediated lysosomal biogenesis. Together, we hope to define STING as a new drug target in lysosomal diseases. This study will also establish a new clinical paradigm for considering STING antagonists as first-line therapy for many lysosomal storage disorders.