Rassu, Mauro (2017) LRRK2 effect on dopamine receptor trafficking: implication in Parkinson’s disease. Doctoral Thesis.
Parkinson disease is the second most common neurodegenerative disorder affecting 4 million people worldwide. It is characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and by the presence of cytoplasmic inclusion bodies (Lewy bodies). Cell death leads to a profound depletion of dopamine neurotransmitter involved mainly in the control of the movement. Mutations in LRRK2 (leucine-rich repeat kinase 2) gene (PARK8; OMIM 609007) are responsible for one of the autosomal-dominant forms of Parkinson’s disease. Up to date, the LRRK2 biological function is largely unknown. LRRK2 has been found in different subcellular districts that play a crucial role in the control of vesicular trafficking: ER, Golgi apparatus and associated vesicles, cytoskeleton, lipid raft and lysosomes. The results of this work indicates that PD-associated mutant G2019S LRRK2 impairs dopamine receptor D1 internalization, leading to an alteration in signal transduction. Moreover, the mutant forms of LRRK2 affect dopamine receptor D2 turnover by decreasing the rate of the receptor trafficking from the Golgi complex to the cell membrane. Collectively, these findings are consistent with the conclusion that LRRK2 influences the motility of neuronal vesicles and the neuronal receptor trafficking.
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