Lysosomal Glucocerebrosidase is needed for ciliary Hedgehog signaling: A convergent pathway to Parkinson’s disease
Published June 26, 2025
Output Details
Preprint January 22, 2025
Published June 26, 2025
Description
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.
Identifier (DOI)
10.1073/pnas.2504774122
