Leucine-rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule-associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism.

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 (MAP

SUBMITTER: Chen K 

PROVIDER: S-EPMC10661827 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature