Function and dysfunction of the Parkinson’s disease kinase LRRK2 at the pre-synaptic site

The LRRK2 gene provides instructions for coding a large protein termed Leucine-rich repeat kinase 2 (LRRK2). LRRK2 is present in the brain and other tissues throughout the body, but little is known about its function. LRRK2 contains an enzymatic activity known as a kinase. Proteins with kinase activity assist in the transfer of a phosphate group to specific amino acids of target proteins. This phosphate transfer, called phosphorylation, is a common mechanism that proteins adopt to communicate and execute different cell programs. Mutations within the kinase domain of LRRK2 cause a genetic form of parkinsonism which accounts for approximately 1-2% of all PD cases. Although patients with LRRK2 mutations usually respond to levodopa therapy, this treatment is only symptomatic and it does not cure the cause of the disease. In particular, LRRK2 mutations lead to neuronal cell death and LRRK2 kinase activity seems to be responsible for the observed neurotoxicity. Therefore, LRRK2 kinase activity is a promising target for pharmacological inhibition. Our precedent research pointed out that LRRK2 is part of a complex signalling pathway that modulates neuron activity acting on the mechanism that regulates nervous signal transmission On these premises, our project aims to define how mutations affecting LRRK2 kinase activity have a direct impact on neuronal functions and if we can pharmacologically counteract these defects.