Neural stem cell culture model for LRRK2 function determines regulation of dopaminergic and microtubule-associated genes

Leucine-rich repeat kinase 2 (Lrrk2) is a Parkinson's disease (PD)-related protein involved in sporadic and familial cases of the disease. Lrrk2 is a kinase and may be involved in intracellular signaling pathways. We established a neural stem cell (NSC)-based model system for Lrrk2-associated PD. We investigated its physiological and pathophysiological expression in human and mouse brain and NSCs using different antibodies defining dopaminergic NSCs as a relevant cells population to study Lrrk2 dysfunction. Using small interfering RNA duplexes targeting Lrrk2 in fetal mouse NSCs, we observed higher Tyrosine hydroxylase (Th) mRNA levels. Conversely, when overexpressing human LRRK2 in fetal mouse NSCs, Th, mRNA levels were reduced. Interestingly, in mutant LRRK2 overexpression Map2 and Kif3A mRNA levels were reduced. In conclusion, we demonstrate that overexpressing LRRK2 in neural stem cells results in a cell culture model for LRRK2-mediated PD. Lrrk2 is conversely linked to Th expression and expression of microtubule genes, implicating a role in the pathomechanism towards dopaminergic neurodegeneration.