Nrf2 Expression Is Decreased in LRRK2 Transgenic Mouse Brain and LRRK2 Overexpressing SH-SY5Y Cells.

Mutations in leucine rich-repeat kinase 2 (LRRK2) cause autosomal-dominant, late-onset Parkinson's disease (PD). Accumulating evidence indicates that PD-associated LRRK2 mutations induce neuronal cell death by increasing cellular reactive oxygen species levels. However, the mechanism of increased oxidative stress associated with LRRK2 kinase activity remains unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that protects cells from oxidative stress by inducing the expression of antioxidant genes. In the present, it was found that decreased expression of Nrf2 and mRNA expression of its target genes in Lrrk2-transgenic mouse brain and LRRK2 overexpressing SH-SY5Y cells. Furthermore, knockdown of glycogen synthase kinase-3β (GSK-3β) recovered Nrf2 expression and mRNA expression of its target genes in LRRK2 overexpressing SH-SY5Y cells. We concluded that since Nrf2 is transcriptional factor for antioxidative responses, therefore, reduction of Nrf2 expression by LRRK2 may be part of a mechanism that LRRK2-induces vulnerability to oxidative stress in neuronal cells.