Leucine-rich repeat kinase 2, synaptic morphology and motor behavior

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known to cause late-onset, familial forms of Parkinson’s Disease, with prevalence up to 40% in specific populations. These mutations are also linked to sporadic PD, highlighting the importance of the related protein in the development of the disease. LRRK2 is a large, complex, multi-domain protein, with two main enzymatic activities: a GTPase domain (bearing three pathogenic mutations) and a kinase domain, in which the most common mutation (G2019S) is found. Even though the precise cellular functions of LRRK2 are not known, LRRK2 has been proposed to take part in key signaling pathways, ultimately governing cellular functions such as synaptic transmission, synaptic vesicle dynamics, autophagy and membrane-to-Golgi trafficking. Major efforts have been dedicated to development and characterization of animal models of LRRK2-induced parkinsonism. However, transgenic models reported so far failed in showing parkinsonian phenotype and neuropathology. In this work, we used three different mouse lines (non-transgenic, BAC hLRRK2-G2019S and LRRK2 knockout) to explore spontaneous and physiologically-stimulated motor behavior as well motor responses to dopaminergic compounds. We found that the G2019S mutation leads to motor impairment which is responsive to dopamine agonists, while ablation of the protein causes hyperactivity and reduced anxious-like behavior. Moreover, mice expressing the G2019S mutation and knockout mice showed opposite responses to dopamine receptor stimulation. In order to investigate the role of endogenous LRRK2 on synaptic morphology and connectivity, we co-cultured striatal medium spiny neurons (MSN) and cortical neurons and applied the LRRK2 kinase inhibitor LRRK2-IN1. We observed a tendency for an increased presynaptic drive towards MSNs and reduction of their postsynaptic receptiveness. These results show that LRRK2 is profoundly involved in regulation of motor and non-motor behavior, with pathogenic mutation leading to the development of a parkinsonian phenotype. This role of LRRK2 is intimately associated with dopamine machinery. We also propose LRRK2 to participate in the maintenance and regulation of cortico-striatal synapses in vitro.