LRRK plays an essential, cell-intrinsic role in the protection of dopaminergic neurons during aging, and new genetic findings suggest that LRRK2 mutations may impair its function, leading to dopaminergic neurodegeneration in PD.
Edmundo G Vides, Ayan Adhikari ... Suzanne R Pfeffer
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.
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.
Herschel S Dhekne, Francesca Tonelli ... Suzanne R Pfeffer
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.
Herschel S Dhekne, Izumi Yanatori ... Suzanne R Pfeffer
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.
Christian Galicia, Giambattista Guaitoli ... Wim Versées
Conformation-specific nanobodies enable to capture and solve the first GTP-bound active structure of a bacterial homolog of the Parkinson-associated LRRK2 protein, providing insights into the activation mechanism of these proteins.
