LRRK2 kinase in Parkinson’s Disease

A subset of Rab GTPases is phosphorylated by pathogenic, mutant forms of LRRK2 kinase. Together with our collaborators, we discovered that LRRK2 phosphorylation of Rab8A and Rab10 blocks the formation of primary cilia in cell culture and certain regions of the brain. We discovered that cholinergic interneurons in the striatum of LRRK2 mutant mice lose their ability to sense Sonic hedgehog because they are less ciliated. Under stress, dopaminergic neurons secrete Sonic hedgehog that is sensed by cholinergic interneurons that send back neuroprotective GDNF. This circuit is predicted to be compromised in Parkinson's disease. We have also helped characterize the newly discovered Rab-specific phosphatase that reverses their LRRK2 phosphorylation. Our most recent work also detects changes in striatal astrocyte cilia.

We have made important contributions to our understanding of the molecular basis of Niemann Pick Type C disease and the mechanism and function of NPC1, a protein that exports LDL-derived cholesterol from lysosomes. We showed that NPC1 lumenal domain 2 helps NPC2 transfer cholesterol onto NPC1 for export. With Kartik Chandran, we showed that our soluble NPC1 domain 2 can block Ebola virus entry. We have provided evidence that NPC1 functions to help cholesterol gain access to the lysosome membrane bilayer that is normally covered by a glycocalyx that is thought to protect the membrane from the action of degradative enzymes. We succeeded in obtaining a crystal structure for NPC2 bound to NPC1 domain 2, published our discovery that LAMP proteins bind cholesterol directly, and recently provided critical detail to the molecular mechanism of cholesterol transport by NPC1 across the lysosomal membrane bilayer. We are currently trying to understand the role of the unusual lysosomal lipid, bis(monoacylglycero)phosphate in regulating lysosomal cholesterol and its additional role as a potential Parkinson's disease biomarker.