Del Giudice, Maria Grazia (2014) LRRK2: an important player in Parkinson's disease: role in vesicle and receptor trafficking. Doctoral Thesis.
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. To date, the physiological and pathological functions of LRRK2 are not clearly defined. This thesis work analyses the role of LRRK2 in controlling vesicle and receptor trafficking in different cellular or animal models and using various readouts. In summary, the main results are the following: in neuronal cells, the presence of LRRK2 G2019S pathological mutant determines increased extracellular dopamine levels either under basal conditions or upon nicotine stimulation; moreover, mutant LRRK2 affects the levels of dopamine receptor D1 (DRD1) on the membrane surface in neuronal cells or animal models. Ultrastructural analysis of PC12-derived cells expressing mutant LRRK2 G2019S shows an altered intracellular vesicle distribution. Finally, in a functional redundancy study, I demonstrate that LRRK1, the closest homologue to LRRK2, affects EGF receptor (EGFR) trafficking while LRRK2 does not play any role in this mechanism. Taken together these results point to a key role of LRRK2 in the control of vesicle trafficking in neuronal cells and highlight a different functional role of the two LRRK proteins.
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