Your browser doesn't support javascript.
loading
Leucine-rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule-associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism.
Chen, Kang; Tang, Fei; Du, Bin; Yue, Zhe-Zhou; Jiao, Ling-Ling; Ding, Xu-Long; Tuo, Qing-Zhang; Meng, Jie; He, Si-Yu; Dai, Lunzhi; Lei, Peng; Wei, Xia-Wei.
Afiliación
  • Chen K; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Tang F; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Du B; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Yue ZZ; Guizhou Yiluoqini Techno. Co., Ltd, Guizhou Shuanglong Airport Economic Zone Guiyang P. R. China.
  • Jiao LL; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Ding XL; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Tuo QZ; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Meng J; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • He SY; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Dai L; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Lei P; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
  • Wei XW; Department of Neurology and State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital, Sichuan University, and Collaborative Center for Biotherapy Chengdu P. R. China.
MedComm (2020) ; 4(6): e429, 2023 Dec.
Article en En | MEDLINE | ID: mdl-38020716
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.
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: MedComm (2020) Año: 2023 Tipo del documento: Article Pais de publicación: China
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: MedComm (2020) Año: 2023 Tipo del documento: Article Pais de publicación: China