Abstract 1329 Accessible cholesterol in Parkinson's Disease

Mutations in LRRK2 kinase and Glucocerebrosidase (GBA1) represent the most common causes of inherited Parkinson's disease. We showed previously that pathogenic LRRK2 mutations interfere with cilia formation in interneurons and astrocytes of the mouse dorsal striatum, leading to defective Hedgehog signaling and consequent loss of neuroprotective GDNF and NRTN to support dopamine neurons. We show here that GBA1 mutations also block Hedgehog signaling in these neurons by a different mechanism. Hedgehog signaling requires primary cilia and a pool of chemically accessible cholesterol in the ciliary membrane outer leaflet.