期刊
NEUROBIOLOGY OF AGING
卷 99, 期 -, 页码 65-78出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2020.12.001
关键词
Dopamine D3 receptor; Heteromerization; Nicotinic receptor; Human induced pluripotent stem cell (iPSC); Parkinson's disease; LRRK2 G2019S
资金
- University of Brescia
- C. Golgi Foundation, Brescia, Italy
- European Union [668738]
Mutations in the LRRK2 gene can lead to abnormal membrane localization of dopamine receptors and nicotinic acetylcholine receptors, potentially contributing to the vulnerability of dopaminergic neurons.
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 D3RnAChR 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. (C) 2020 Elsevier Inc. All rights reserved.yy
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