Recruitment of TFs to the aggregates may result in loss of functions of the TFs. Functional consequence of such recruitment remains largely unknown. Transcription factors (TFs) like TBP, CBP, p53, Sp1, NFkB and others are recruited to aggregates formed by mutant HTT, the hallmark of HD –. Such deregulation of genes has been attributed, at least partially, to interactions and recruitments of several transcription factors to the mutant HTT aggregates. Among various molecular and cellular dysfunctions originated from mutations to HTT gene, which eventually lead to neuronal loss from striatal regions in HD patients, transcriptional deregulation is considered to be one of the important events. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of polymorphic CAG repeats in exon1 of Huntingtin ( HTT) gene. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by the Institutional Grant to Saha Institute of Nuclear Physics for the Project ‘Structural Proteomics and Genomics of Human Genetic Diseases’ by the Department of Atomic Energy, Government of India. Received: DecemAccepted: JPublished: August 26, 2011Ĭopyright: © 2011 Ghose et al. Kahle, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, Germany Our observation of interplay between transcription factors and miRNAs using HD cell model provides an important platform upon which further work is to be done to establish if such regulation plays any role in HD pathogenesis.Ĭitation: Ghose J, Sinha M, Das E, Jana NR, Bhattacharyya NP (2011) Regulation of miR-146a by RelA/NFkB and p53 in ST Hdh Q111/ Hdh Q111 Cells, a Cell Model of Huntington's Disease. We conclude that (i) miR-125b and miR-150 target p53, which in turn regulates RelA/NFkB and miR-146a expressions (ii) reduced miR-125b and miR-150 expressions, increased p53 level and decreased RelA/NFkB and miR-146a expressions originate from mutant HTT (iii) p53 directly or indirectly regulates the expression of miR-146a. In a cell model, this effect could be reversed by exogenous expression of chaperone like proteins HYPK and Hsp70. We also demonstrate that expression of p53 is increased and levels of RelA/NFkB, miR-146a, miR-150 and miR-125b are decreased in striatum of R6/2 mice, a mouse model of HD and in cell models of HD. Elevated p53 interacts with RelA/NFkB, reduces its expression and activity and decreases the expression of miR-146a, while knocking down p53 increases RelA/NFkB and miR-146a expressions. This partially explains the up regulation of p53 observed in HD. By reporter luciferase assay, RT-PCR and western blot analysis, we also show that both miR-150 and miR-125b target p53. In the present manuscript, we show by luciferase reporter assays and real time PCR that decreased miR-146a expression in ST Hdh Q111/ Hdh Q111 cells is due to decreased expression and activity of p65 subunit of NFkB (RelA/NFkB). We observed earlier that expressions of miR-125b, miR-146a and miR-150 are decreased in ST Hdh Q111/ Hdh Q111 cells, a model for HD in comparison to those of wild type ST Hdh Q7/Hdh Q7 cells. Deregulated microRNAs and loss of function of transcription factors recruited to mutant HTT aggregates could cause characteristic transcriptional deregulation associated with HD.

Huntington's disease (HD) is caused by the expansion of N-terminal polymorphic poly Q stretch of the protein huntingtin (HTT).

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