Leucine‐rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule‐associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism
Kang Chen,
Fei Tang,
Bin Du,
Zhe‐Zhou Yue,
Ling‐Ling Jiao,
Xu‐Long Ding,
Qing‐Zhang Tuo,
Jie Meng,
Si‐Yu He,
Lunzhi Dai,
Peng Lei,
Xia‐Wei Wei
Affiliations
Kang Chen
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Fei Tang
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Bin Du
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Zhe‐Zhou Yue
Guizhou Yiluoqini Techno. Co., Ltd, Guizhou Shuanglong Airport Economic Zone Guiyang P. R. China
Ling‐Ling Jiao
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Xu‐Long Ding
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Qing‐Zhang Tuo
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Jie Meng
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Si‐Yu He
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Lunzhi Dai
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Peng Lei
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Xia‐Wei Wei
Department of Neurology and State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China Hospital, Sichuan University, and Collaborative Center for BiotherapyChengdu P. R. China
Abstract Mutations in LRRK2 (encoding leucine‐rich repeat kinase 2 protein, LRRK2) are the most common genetic risk factors for Parkinson's disease (PD), and increased LRRK2 kinase activity was observed in sporadic PD. Therefore, inhibition of LRRK2 has been tested as a disease‐modifying therapeutic strategy using the LRRK2 mutant mice and sporadic PD. Here, we report a newly designed molecule, FL090, as a LRRK2 kinase inhibitor, verified in cell culture and animal models of PD. Using the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mice and SNCA A53T transgenic mice, FL090 ameliorated motor dysfunctions, reduced LRRK2 kinase activity, and rescued loss in the dopaminergic neurons in the substantia nigra. Notably, by RNA‐Seq analysis, we identified microtubule‐associated protein 1 (MAP1B) as a crucial mediator of FL090's neuroprotective effects and found that MAP1B and LRRK2 co‐localize. Overexpression of MAP1B rescued 1‐methyl‐4‐phenylpyridinium induced cytotoxicity through rescuing the lysosomal function, and the protective effect of FL090 was lost in MAP1B knockout cells. Further studies may be focused on the in vivo mechanisms of MAP1B and microtubule function in PD. Collectively, these findings highlight the potential of FL090 as a therapeutic agent for sporadic PD and familial PD without LRRK2 mutations.
