Lysosomal Glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway to Parkinson’s disease

Mutations in LRRK2 and GBA1 are the most common genetic causes of familial Parkinson’s disease. Previously, we showed that pathogenic LRRK2 mutations inhibit primary cilia formation in rare interneurons and astrocytes of the mouse and human dorsal striatum. This blocks Hedgehog signaling and reduces synthesis of neuroprotective GDNF and NRTN, which support neurons vulnerable in PD. Here we show that GBA1 mutations also impair Hedgehog signaling through a distinct mechanism. Loss of GBA1 activity decreases accessible cholesterol in primary cilia of cultured cells, thereby disrupting Hedgehog signaling. In the mouse striatum, Gba1 mutations result in reduced Hedgehog-induced Gdnf RNA expression in cholinergic interneurons, despite having no detectable impact on cilia formation. Also, both Lrrk2 and Gba1 mutations suppress Hedgehog-induced Bdnf expression in striatal astrocytes. These findings underscore the role of Hedgehog signaling in the nigrostriatal circuit and reveal a convergent mechanism by which distinct mutations may contribute to PD pathogenesis.