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Nrf2 Expression Is Decreased in LRRK2 Transgenic Mouse Brain and LRRK2 Overexpressing SH-SY5Y Cells
Fumitaka Kawakami1,2,3, Motoki Imai3,4, Shun Tamaki1,3
1Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University.
Abstract:
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.
Insights
Parkinson's disease (PD) mutations in leucine-rich repeat kinase 2 (LRRK2) reduce the protective Nrf2 antioxidant response. This LRRK2-mediated decrease in Nrf2 may increase neuronal vulnerability to oxidative stress.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mutations in leucine-rich repeat kinase 2 (LRRK2) are a key cause of autosomal-dominant Parkinson's disease (PD).
- LRRK2 mutations are linked to increased cellular reactive oxygen species (ROS) and neuronal cell death, but the underlying mechanism is unclear.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor that combats oxidative stress by upregulating antioxidant genes.
Purpose of the Study:
- To investigate the mechanism by which LRRK2 mutations contribute to oxidative stress in Parkinson's disease.
- To determine the role of Nrf2 in LRRK2-induced neuronal vulnerability.
Main Methods:
- Examined Nrf2 expression and its target gene mRNA levels in Lrrk2-transgenic mouse brains.
- Assessed Nrf2 expression and target gene mRNA in LRRK2-overexpressing SH-SY5Y cells.
- Investigated the effect of glycogen synthase kinase-3β (GSK-3β) knockdown on Nrf2 expression in LRRK2-overexpressing cells.
Main Results:
- Decreased expression of Nrf2 and its target genes was observed in both Lrrk2-transgenic mouse brains and LRRK2-overexpressing SH-SY5Y cells.
- Knockdown of GSK-3β restored Nrf2 expression and its target gene expression in LRRK2-overexpressing SH-SY5Y cells.
- These findings suggest a link between LRRK2 activity, GSK-3β, and Nrf2 regulation.
Conclusions:
- LRRK2-mediated reduction of Nrf2 expression may be a significant factor in the increased susceptibility of neuronal cells to oxidative stress in Parkinson's disease.
- Targeting the LRRK2-GSK-3β-Nrf2 pathway could offer a novel therapeutic strategy for Parkinson's disease.
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