The Leucine Rich Repeat Kinase (LRRK2) protein is a large multidomain protein with unknown function. Through genetic analysis of large familial cohorts we have discovered that mutations in the gene coding LRRK2 causes the largest number of familial and idiopathic cases of Parkinson’s Disease (PD) identified to date. Furthermore, histological analyses of the brains of LRRK2 carriers show tau and α-synuclein pathology, key hallmarks of PD and implicating it heavily in the disorder.
While the normal physiological function has yet to be fully discerned, there has been evidence that LRRK2 has a role in neurotransmission in non-mammalian systems as well as neuronal and synaptic morphology. It is crucial that the physiological role of LRRK2 be fully elucidated in order to understand the effect mutations in the protein may contribute to disease.
We hypothesize that LRRK2 has an important role in synaptic architecture and efficacy of mammalian systems and that mutation(s) to the protein will result in a subtle synaptic phenotype that will, over time, result in a cumulative effect manifesting as the clinical phenotype observed in PD.
Aims & Expected Results
We are currently using appropriate animal models to assess the physiological role of LRRK2 in synaptic transmission. Moreover, we are also investigating the impact the common G2019S LRRK2 mutation has on this normal physiological function.
We are using primary cultures from these models to assess the function of normal and mutant LRRK2 in the regulation of neuronal morphology. Furthermore, cultures will be used in order to assess the viability of acute manipulation using pharmacological tools in order to identify suitable therapeutic targets.
Initial data has shown that LRRK2 has a subtle yet significant role in neurotransmitter release and synaptic maintenance that is perturbed by the G2019S mutation.