期刊
TOXICOLOGICAL SCIENCES
卷 176, 期 2, 页码 433-445出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfaa066
关键词
rotenone; miR-146a; Parkin; mitochondria; mitophagy; neurodegeneration
类别
资金
- SERB, New Delhi [GAP359]
- Council of Scientific and Industrial Research (CSIR) Network Project (miND) [BSC115]
Mitochondrial dysfunction is a common cause in pathophysiology of different neurodegenerative diseases. Elimination of dysfunctional and damaged mitochondria is a key requirement for maintaining homeostasis and bioenergetics of degenerating neurons. Using global microRNA (miRNA) profiling in a systemic rotenone model of Parkinson's disease, we have identified miR-146a as upmost-regulated miRNA, which is known as inflammation regulatory miRNA. Here, we report the role of activated nuclear factor kappa beta (NF-k beta) in miR-146a-mediated downregulation of Parkin protein, which inhibits clearance of damaged mitochondria and induces neurodegeneration. Our studies have shown that 4-week rotenone exposure (2.5 mg/kg b.wt) induced oxidative imbalance-mediated NF-k beta activation in 1-year-old rat's brain. Activated NF-k beta binds in promoter region of miR-146a gene and induces its transcription, which downregulates levels of Parkin protein. Decreased amount of Parkin protein results in accumulation of damaged and dysfunctional mitochondria, which further promotes the generation of reactive oxygen species in degenerating neurons. In conclusion, our studies have identified direct role of NF-k beta-mediated upregulation of miR-146a in regulating mitophagy through inhibition of the Parkin gene.
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