Parkinson’s disease-associated LRRK2 kinase is recruited to membranes by its Rab GTPase substrates, and LRRK2 is both retained on membranes and further activated there by cooperative interaction with the phosphorylated Rab proteins that it generates.

PPM1H protein phosphatase dephosphorylates Rab proteins modulating LRRK2 signalling.

Although human Parkinson's disease is linked to dopamine loss, two distinct mutations in a kinase associated with familial Parkinson's operate downstream, altering excitatory synapses on dopamine-sensing neurons.

Activating mutations in the leucine-rich repeat kinase 2 cause Parkinson’s disease, and an unbiased genome-wide screen revealed an unexpected, specific role for Rab12 in activating this kinase directly for Rab GTPase phosphorylation.

Striatal cholinergic interneurons and astrocytes lose cilia and show dysregulation of Hedgehog signaling in mice with a Parkinson's disease-associated, G2019S LRRK2 mutation or upon loss of PPM1H phosphatase specific for LRRK2-phosphorylated Rab GTPases.

The traditional herbal medicine Gastrodia elata Blume, in the water-extracted form as food supplement, improves locomotion and protects dopaminergic neurons in Lrrk2-G2019S Parkinson’s disease models through Nrf2 activation in glia.

Pathogenic LRRK2kinase requires Rab10 and RILPL1 to block primary cilia formation, shortening cilia on cholinergic neurons needed for a hedgehog driven circuit that supports dopaminergic neurons in mouse brain.

Parkinson's kinase LRRK2 phosphorylates a distinct subset of Rabs, and LRRK2-dependent phosphorylation links LRKK2 to ciliogenesis.

Discovery of a physiological LRRK2 substrate and a new mechanism of Rab regulation should aid Parkinson’s research and the understanding of Rab function.