LRRK2 in Parkinson's disease: function in cells and neurodegeneration

The detailed characterization of the function of leucine-rich repeat kinase 2 (LRRK2) may provide insight into the molecular basis of neurodegeneration in Parkinson's disease (PD) because mutations in LRRK2 cause a phenotype with strong overlap to typical late-onset disease and LRRK2 mutations are responsible for significant proportions of PD in some populations. The complexity of large multidomain protein kinases such as LRRK2 challenges traditional functional approaches, although initial studies have successfully defined the basic mechanisms of enzyme activity with respect to the putative effects of pathogenic mutations on kinase activity. The role of LRRK2 in cells remains elusive, with potential function in mitogen-activated protein kinase pathways, protein translation control, programmed cell death pathways and activity in cytoskeleton dynamics. The initial focus on LRRK2-kinase-dependent phenomena places emphasis on the discovery of LRRK2 kinase substrates, although candidate substrates are so far confined to in vitro assays. Here, hypothetical mechanisms for LRRK2-mediated cell death and kinase activation are proposed. As a promising target for neuroprotection strategies in PD, in vitro and in vivo models that accurately demonstrate LRRK2's function relevant to neurodegeneration will aide in the identification of molecules with the highest chance of success in the clinic.