Bichler Zoë, Vanan Sarivin, Zhang Zhiwei, Dong Qianying Sally, Lee Jolene Wei Ling, Zhang Chengwu, Hang Liting, Jiang Mei, Padmanabhan Parasuraman, Saw Wuan Ting, Zhou Zhidong, Gulyás Balázs, Lim Kah Leong, Zeng Li, Tan Eng King
Behavioural Neuroscience Lab, Research Department, National Neuroscience Institute, Singapore 308433, Singapore.
Center for Biometric Analysis, The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Int J Mol Sci. 2025 Apr 10;26(8):3556. doi: 10.3390/ijms26083556.
Parkinson's disease (PD) is a neurodegenerative disorder affecting nearly 10 million people worldwide, and for which no cure is currently known. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene, age, as well as environmental factors such as neurotoxin exposure and stress, are known to increase the risk of developing the disease in humans. To investigate the role of a specific Asian variant of the LRRK2 gene to induce susceptibility to stress and trigger PD phenotypes with time, knock-in (KI) mice bearing the human LRRK2 R1628P risk variant have been generated and studied from 2 to 16 months of age in the presence (or absence) of stress insults, including neurotoxin injections and chronic mild stress applied at 3 months of age. Pathophysiological and behavioural phenotypes have been measured at different ages and primary neurons and fibroblast cells were cultured from the KI mouse line and treated with HO to study susceptibility towards oxidative stress . KI mice displayed specific PD features and these phenotypes were aggravated by environmental stresses. In particular, KI mice developed locomotion impairment and increased constipation. In addition, dopamine-related proteins were dysregulated in KI mice brains: Dopamine transporter (DAT) was decreased in the midbrain and striatum and dopamine levels were increased. Primary fibroblast cells and cortical neurons from KI mice also displayed increased susceptibility to oxidative stress. Therefore, the LRRK2 R1628P KI mice are an excellent model to study the progressive development of PD.
帕金森病（PD）是一种神经退行性疾病，全球近1000万人受其影响，目前尚无治愈方法。已知富含亮氨酸重复激酶2（LRRK2）基因的突变、年龄以及环境因素（如接触神经毒素和压力）会增加人类患该病的风险。为了研究LRRK2基因的一种特定亚洲变体在诱导对压力的易感性以及随时间触发PD表型方面的作用，已培育出携带人类LRRK2 R1628P风险变体的基因敲入（KI）小鼠，并在2至16个月龄时，在有（或无）压力刺激的情况下进行研究，压力刺激包括在3个月龄时注射神经毒素和施加慢性轻度应激。在不同年龄测量了病理生理和行为表型，并从KI小鼠品系中培养了原代神经元和成纤维细胞，用HO处理以研究对氧化应激的易感性。KI小鼠表现出特定的PD特征，并且这些表型因环境压力而加重。特别是，KI小鼠出现运动障碍和便秘增加。此外，KI小鼠大脑中与多巴胺相关的蛋白质失调：中脑和纹状体中的多巴胺转运体（DAT）减少，多巴胺水平升高。KI小鼠的原代成纤维细胞和皮质神经元对氧化应激的易感性也增加。因此，LRRK2 R1628P KI小鼠是研究PD进行性发展的优秀模型。
