LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells

Background: Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson's disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been established. Cellular senescence is correlated with the dysregulation of the proteolytic pathway and mitochondrial dysfunction, which are also associated with the aggregation of α-synuclein (α-syn).

Methods: Human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) were treated with rotenone in the presence or absence of the LRRK2 kinase inhibitor GSK2578215A (GSK-KI) for 48 h. The markers of cellular senescence, including p53, p21Waf1/Cip1 (p21), β-galactosidase (β-gal), Rb phosphorylation, senescence-associated (SA) β-gal activity, and lysosomal activity, were examined. The dSH cells and rat primary cortical neurons were treated with α-syn fibrils 30 min before treatment with rotenone in the presence or absence of GSK-KI for 48 h. Mice were intraperitoneally injected with rotenone and MLi-2 (LRRK2 kinase inhibitor) once every two days for two weeks.

Results: Rotenone upregulated LRRK2 phosphorylation and β-gal levels through the activation of the p53-p21 signaling axis and downregulated Rb phosphorylation. Additionally, rotenone upregulated SA β-gal activity, reactive oxygen species levels, and LRRK2 phosphorylation and inhibited lysosome activity. Rotenone-induced LRRK2 upregulation impaired the clearance of α-syn fibrils. Treatment with LRRK2 inhibitor mitigated rotenone-induced cellular senescence and α-syn accumulation.

Conclusions: Rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, which enhanced α-syn accumulation. However, the administration of an LRRK2 kinase inhibitor rejuvenated rotenone-induced cellular senescence.

 

Comments:

The study you've outlined seems to explore the relationship between LRRK2, cellular senescence, and the accumulation of α-synuclein (α-syn), particularly in the context of Parkinson's disease (PD) pathogenesis. The findings suggest that rotenone, a chemical known to induce PD-like symptoms in animal models, triggers an upregulation of LRRK2 phosphorylation, leading to cellular senescence. This, in turn, exacerbates the accumulation of α-syn, a hallmark of PD.

The methods employed involved using differentiated SH-SY5Y cells and rat primary cortical neurons treated with rotenone and α-syn fibrils in the presence or absence of LRRK2 kinase inhibitors. The results demonstrated that inhibiting LRRK2 kinase activity with GSK2578215A (GSK-KI) or MLi-2 mitigated rotenone-induced cellular senescence and reduced α-syn accumulation.

The study implies a potential link between LRRK2, cellular senescence, and α-syn accumulation in PD pathogenesis. Targeting LRRK2 kinase activity might hold promise as a therapeutic approach to mitigate cellular senescence and α-syn accumulation in PD models induced by rotenone.