Molecular Mechanisms of LRRK1 Regulation of Bone Homeostasis

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Project Summary/Abstract Leucine rich repeat kinase 1 (LRRK1), a novel serine/threonine kinase, is expressed in bones, brain and other tissues. We recently demonstrated that Lrrk1 gene knockout (KO) mice as well as a patient with a Lrrk1 gene mutation are severely osteopetrotic due to osteoclast dysfunction and reduced bone resorption in long and vertebra bones. More importantly, Lrrk1 KO mice had lifelong bone accumulation and responded normally to the anabolic actions of teriparatide treatment but were resistant to ovariectomy (OVX)-induced bone boss. These observations make LRRK1 an ideal target of a novel anti-resorption drugs for treatment of osteoporosis. In this grant, our focus is to perform in vivo and in vitro studies to study the role of LRRK1-mediated phosphorylation of osteopetrosis specific transmembrane protein 1 (OSTM1) in the regulation of chloride channel 7 (CLC7) complex stabilization, lysosomal peripheral movement, lysosomal acid secretion and OC function. To this end, we hypothesize that LRRK1 phosphorylation of OSTM1 at residues of threonine 328 and serine 329 regulates OC function and bone resorption by stabilization of OSTM1/CLC7 complex and promotion of lysosomal peripheral movement and lysosomal acid secretion into lacuna in vivo. Four-year studies proposed in this grant will deliver the role of LRRK1 phosphorylation of threonine and serine residues of OSTM1 in regulation of bone resorption in vitro and in vivo. The results of this application will help our understanding of molecular mechanisms of LRRK1 and OSTM1 actions in osteoclast and develop potential inhibitors of LRRK1 for treatment of osteoporosis in future.