Role of LRRK2 in the regulation of dopamine receptor trafficking
by Mauro Rassu, Maria Grazia Del Giudice, Simona Sanna, Jean Marc Taymans, Michele Morari, Alberto Brugnoli, Martina Frassineti, Alessandra Masala, Sonia Esposito, Manuela Galioto, Cristiana Valle, Maria Teresa Carri, Alice Biosa, Elisa Greggio, Claudia Crosio, Ciro Iaccarino
Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking that in turn may regulate different aspects of neuronal physiology. We have analyzed the role of LRRK2 in regulating dopamine receptor D1 (DRD1) and D2 (DRD2) trafficking. DRD1 and DRD2 are the most abundant dopamine receptors in the brain. They differ in structural, pharmacological and biochemical properties, as well as in localization and internalization mechanisms. Our results indicate that disease-associated mutant G2019S LRRK2 impairs DRD1 internalization, leading to an alteration in signal transduction. Moreover, the mutant forms of LRRK2 affect receptor turnover by decreasing the rate of DRD2 trafficking from the Golgi complex to the cell membrane. Collectively, our findings are consistent with the conclusion that LRRK2 influences the motility of neuronal vesicles and the neuronal receptor trafficking. These findings have important implications for the complex role that LRRK2 plays in neuronal physiology and the possible pathological mechanisms that may lead to neuronal death in PD.Publisher URL: http://journals.plos.org/plosone/article
DOI: 10.1371/journal.pone.0179082
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