Parkinson’s disease at the synaptic site: short and long term impact of pathological LRRK2 kinase activity

Mutations in LRRK2 gene cause a familial form of PD which accounts for approximately 1-2% of all PD cases. 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. The commonest LRRK2 mutation, G2019S, increase protein kinase activity. 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. 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 toxic protein aggregates and LRRK2 kinase activity seems to be responsible for the observed neurotoxicity. Our previous research pointed out that LRRK2 is part of a complex signalling pathway that modulates neuron activity via phosphorylation. We found that such phosphorylation in long term induces aberrant protein accumulation. On these premises, our project aims to define how mutations activating LRRK2 kinase function impact on neuronal functions and protein accumulation and if we can pharmacologically counteract these defects.