Impaired dopamine D3 and nicotinic acetylcholine receptor membrane localization in iPSCs-derived dopaminergic neurons from two Parkinson's disease patients carrying the LRRK2 G2019S mutation

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) are the most common genetic determinants of Parkinson's disease (PD), with the G2019S accounting for about 3% of PD cases. LRRK2 regulates various cellular processes, including vesicle trafficking that is crucial for receptor localization at the plasma membrane. In this study, induced pluripotent stem cells derived from 2 PD patients bearing the G2019S LRRK2 kinase activating mutation were used to generate neuronal cultures enriched in dopaminergic neurons. The results show that mutant LRRK2 prevents the membrane localization of both the dopamine D3 receptors (D3R) and the nicotinic acetylcholine receptors (nAChR) and the formation of the D3R-nAChR heteromer, a molecular unit crucial for promoting neuronal homeostasis and preserving dopaminergic neuron health. Interestingly, D3R and nAChR as well as the corresponding heteromer membrane localization were rescued by inhibiting the abnormally increased kinase activity. Thus, the altered membrane localization of the D3R-nAChR heteromer associated with mutation in LRRK2 might represent a pre-degenerative feature of dopaminergic neurons contributing to the special vulnerability of this neuronal population.

Keywords: Dopamine D3 receptor; Heteromerization; Human induced pluripotent stem cell (iPSC); LRRK2 G2019S; Nicotinic receptor; Parkinson’s disease.