Quercetin improves the activity of the ubiquitin‐proteasomal system in 150Q mutated huntingtin‐expressing cells but exerts detrimental effects on neuronal survivability. Issue 10 (8th July 2015)

• Record Type: Journal Article
• Authors: Chakraborty, J.; Rajamma, U.; Jana, N.; Mohanakumar, K.P.
• Is Part Of: Journal of neuroscience research. Volume 93:Issue 10(2015)
• Page Start: 1581
• Page End: 1591
• Publication Date: 2015-07-08
• Subjects: Huntington's disease -- cell death -- ubiquitin‐proteasome system -- mitochondrial membrane potential -- neuroprotection -- quercetin neurotoxicity -- RRID:AB_628423 -- RRID:AB_785340; Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.23618
• Languages: English
• ISSNs: 0360-4012

Abstract

Abstract : Quercetin, a strong free radical scavenger, is investigated for neuroprotective effects in a Neuro 2a cell line conditionally transfected with 16Q huntingtin ( Htt ) and 150Q Htt, which express the protein upon stimulation. Cells were protected from death by a 20‐µM dose of quercetin on the second day of Htt induction, but 30–100‐µM doses of the drug caused further toxicity in both 16Q and 150Q cells, as indicated by MTT assay and by significant reductions in the number of cells bearing neurites on the second day. A significant decrease in the number of cells containing aggregate was seen in induced 150Q cells treated with 20 µM but not for those treated with 40 or 50 µM quercetin up to 4 days of induction. Mutated Htt (mHtt)‐induced reduction in proteasomal activity of the ubiquitin‐proteasomal system (UPS) was significantly attenuated by 20 µM quercetin. However, neither mitochondrial membrane potential loss nor colocalization of 20S proteasome with mHtt aggregate was corrected by quercetin treatment. Our results imply that the neuroprotective effect of quercetin arises out of the upregulation of UPS activity, which causes a decrease in the number of mHtt aggregate‐harboring cells. The increased neurotoxicity could result from the continued association of mHtt with 20S proteasome and the failure of quercetin to correct mitochondrial membrane potential loss. These results suggest that, although quercetin at a low dose protects against mHtt‐mediated cell death, higher doses are toxic to the cells, clearly demarcating a narrow therapeutic window for this dietary flavonoid. © 2015 Wiley Periodicals, Inc. Abstract : A dietary polyphenol, quercetin, protected cells against huntingtin aggregate‐mediated cellular toxicity at lower doses, but higher doses were found to be detrimental. Quercetin at lower doses showed no effects on survivability of Neuro 2a and SH‐SY5Y cells that do not express mutant huntingtin but was toxic at higher doses.