Based on previous reports and our own research, we discuss in this review the potential role of HSF1 in mediating mitochondrial dysfunction in HD and propose a unifying mechanism that integrates the responses mediated by p53 and PGC-1α in HD <i>via</i> HSF1.
Transient knock-down of Meg3 and Neat1 in cell models of HD led to a significant decrease of aggregates formed by mutant huntingtin and downregulation of the endogenous Tp53 expression.
Therefore, we aimed to generate HD iPS cells with stable silencing of HTT and further to investigate the effects of HTT knock-down on deregulations of signaling pathways e.g., p53 downregulation, present in cells already in pluripotent state.
Together, we propose that Wig1, a key p53 downstream molecule in HD condition, play an important role in stabilizing mutant Htt mRNA and thereby accelerating HD pathology in the mHtt-p53-Wig1 positive feedback manner.
We conclude that the disease causing mutation in HD increases the propensity of chromosomal instability relative to control fibroblasts specifically during reprogramming to a pluripotent state by a commonly used episomal-based method that includes p53 knockdown.
Interestingly, a common protein interactor of the huntingtin protein and the proteins in the above pathways is p53, and the expression of p53 was dysregulated in HD YAC128 iPSCs and human HD iPSCs.
We assessed cellular manganese handling to test for correlations with the ATM-p53 pathway, and we observed reduced Mn accumulation in HD human neuroprogenitors and HD mouse striatal cells at manganese exposures associated with altered p53 activation.
Mutation of Huntingtin (HTT) which causes Huntington's disease (HD) and mutations to TP53 which is associated with different cancers are studied as two example cases.
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.
The analysis of the upstream regulatory regions in co-regulated miRNAs suggests a role for RE1-Silencing Transcription Factor (REST) and P53 in miRNAs downregulation in HD.
These results demonstrate that p53 protein can regulate huntingtin expression at transcriptional level, and suggest that a p53 stress response could be a modulator of the process of Huntington's disease.
Huntington's disease (HD) is a polyglutamine disorder whose pathogenesis likely involves mitochondrial dysfunction.In this issue of Neuron, Bae et al. present data implicating p53 in HD pathogenesis.
Age at onset of Huntington disease is not modulated by the R72P variation in TP53 and the R196K variation in the gene coding for the human caspase activated DNase (hCAD).
There is growing evidence that truncated forms of mutant Htt in the nucleus influence gene transcription by binding to proteins such as CREB binding protein (CBP) response element binding protein binding protein, N-COR, glyceraldehyde-3-phosphate dehydrogenase, and p53. p53 regulates the transcription of various mitochondrial proteins which may underlie the mitochondrial abnormalities, especially the vulnerability to mitochondrial depolarization, seen in HD tissues.