Convergent molecular pathways to inherited Parkinson's disease.

The most common, high-risk genetic factors for Parkinson's disease are pathogenic LRRK2 variants that increase LRRK2 kinase activity and pathogenic GBA1 variants that reduce lysosomal glucocerebrosidase activity. LRRK2 phosphorylates a subset of Rab GTPases, enabling them to bind phosphorylation-specific effectors that drive cellular pathology. To date, LRRK2 has at least two major cellular roles: it promotes exocytosis of lysosome-related organelles-particularly under conditions of lysosome stress in macrophages and microglia-and it regulates the formation and stabilization of primary cilia in neurons and astrocytes. In the brain, loss of primary cilia or GBA1 deficiency impairs Hedgehog signaling, reducing production of neuroprotective factors needed to support vulnerable dopamine neurons. Remarkably, administration of a LRRK2 inhibitor to LRRK2 mutant mice restores cilia and rescues neuroprotective factor production, offering great promise for people with Parkinson's.