Coordinated action of miR-146a and Parkin gene regulate Rotenone-induced neurodegeneration.

: 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 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 in miR-146a mediated down-regulation 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-kB activation in 1 year aged rat's brain. Activated NF-kB binds in promoter region of miR-146a gene and induced its transcription, which down-regulates 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-kB mediated up-regulation of miR-146a in regulating mitophagy through inhibition of the parkin gene.