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RNAi-mediated knockdown of DJ-1 leads to mitochondrial dysfunction via Akt/GSK-3ß and JNK signaling pathways in dopaminergic neuron-like cells.
- Source :
-
Brain Research Bulletin . Mar2019, Vol. 146, p228-236. 9p. - Publication Year :
- 2019
-
Abstract
- Highlights • DJ-1 knockdown resulted in mitochondrial dysfunction. • loss of DJ-1 suppressed Akt pathway, and reduced nuclear translocation of Nrf2. • DJ-1 deficiency led to an obvious increase in the ROS level, and then activated JNK signaling. Abstract Deletions or some mutations in the gene encoding the multifunctional protein, DJ-1, have been considered to be linked with autosomal recessive early onset Parkinson's disease (PD). Current emerging evidence suggests that DJ-1 is involved in the protection against oxidative stress-induced mitochondrial damage. However, the exact molecular mechanisms underlying this are not completely clear. The aim of this study was to investigate the effects of DJ-1 on the Akt pathway, nuclear factor erythroid 2-related factor (Nrf2), and c-Jun N-terminal kinase (JNK) with regard to modulating mitochondrial function. Here we showed that knockdown of DJ-1 resulted in mitochondrial dysfunction, including a decrease in active mitochondrial mass, complex I deficits, and inhibition of cellular adenosine 5′-triphosphate (ATP) content in the dopaminergic neuron-like cells PC12 and SH-SY5Y. Additionally, loss of DJ-1 impaired Akt signaling, and reduced nuclear translocation of Nrf2, thereby inhibiting activity of Nrf2-regulated downstream antioxidant enzymes such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. Moreover, DJ-1 knockdown also led to a significant increase in the mitochondrial reactive oxygen species, and then promoted the activation of JNK pathways. Furthermore, oxidative stress and mitochondrial dysfunction induced by knockdown of DJ-1 were blocked by a JNK inhibitor, which confirmed the important role of JNK activation in mitochondrial dysfunction. In conclusion, the present study indicates that DJ-1 knockdown leads to mitochondrial dysfunction in dopaminergic neuron-like cells, at least in part, through suppressing the Akt/GSK3β pathway and impairing the oxidative stress response, as well as through the subsequent increased JNK activation in dopaminergic neuron-like cells. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ADENOSINES
*DELETION mutation
*NAD (Coenzyme)
Subjects
Details
- Language :
- English
- ISSN :
- 03619230
- Volume :
- 146
- Database :
- Academic Search Index
- Journal :
- Brain Research Bulletin
- Publication Type :
- Academic Journal
- Accession number :
- 134688615
- Full Text :
- https://doi.org/10.1016/j.brainresbull.2019.01.007