Role of LRRK2 in the regulation of dopamine receptor trafficking

The leucine-rich repeat kinase 2 (LRRK2) gene was found to play a prominent role in the pathogenesis of both familial and sporadic Parkinson’s disease (PD). LRRK2 encodes a large multi-domain protein that is expressed in different tissues. Up to date, the LRRK2 biological function is largely unknown. LRRK2 appears to be localized in different intracellular districts that play a critical role in the control of vesicular trafficking: ER, Golgi apparatus and associated vesicles, cytoskeleton, lipid raft and lysosomes. Although with some discrepancies between different experimental approaches either in animal or cellular models, the involvement of LRRK2 in the regulation of vesicle trafficking appears quite consistent. In neurons, vesicle trafficking is a complex process regulating multiple different cellular functions, in addition to the neurotransmitter release or re-uptake, such as the localization and levels of membrane receptors, changes in plasma membrane composition at the cell surface and, not least, organelle biogenesis. The major objective of our work is to investigate the role of LRRK2 in controlling dopamine receptor D1 (DRD1) trafficking in cellular and animal model. We have analyzed, in stable SH-SY5Y clones expressing DRD1, the internalization of this receptor upon dopamine treatments and adenoviral delivery of wild type or mutants LRRK2. Preliminary results indicate that expression of wild type or mutant LRRK2 correlates with specific alterations in DRD1 trafficking.