scholarly journals The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice

2008 ◽  
Vol 105 (40) ◽  
pp. 15564-15569 ◽  
Author(s):  
Elizabeth A. Thomas ◽  
Giovanni Coppola ◽  
Paula A. Desplats ◽  
Bin Tang ◽  
Elisabetta Soragni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Hdac Inhibitor ◽  
Brain Size ◽  
Hdac Inhibitors ◽  
Motor Deficits ◽  
Therapeutic Effects ◽  
Mutant Huntingtin

Transcriptional dysregulation has emerged as a core pathologic feature of Huntington's disease (HD), one of several triplet-repeat disorders characterized by movement deficits and cognitive dysfunction. Although the mechanisms contributing to the gene expression deficits remain unknown, therapeutic strategies have aimed to improve transcriptional output via modulation of chromatin structure. Recent studies have demonstrated therapeutic effects of commercially available histone deacetylase (HDAC) inhibitors in several HD models; however, the therapeutic value of these compounds is limited by their toxic effects. Here, beneficial effects of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, in an HD mouse model are reported. Chronic oral administration of HDACi 4b, beginning after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight of symptomatic R6/2300Q transgenic mice. These effects were associated with significant attenuation of gross brain-size decline and striatal atrophy. Microarray studies revealed that HDACi 4b treatment ameliorated, in part, alterations in gene expression caused by the presence of mutant huntingtin protein in the striatum, cortex, and cerebellum of R6/2300Q transgenic mice. For selected genes, HDACi 4b treatment reversed histone H3 hypoacetylation observed in the presence of mutant huntingtin, in association with correction of mRNA expression levels. These findings suggest that HDACi 4b, and possibly related HDAC inhibitors, may offer clinical benefit for HD patients and provide a novel set of potential biomarkers for clinical assessment.

scholarly journals Motor deficits associated with Huntington's disease occur in the absence of striatal degeneration in BACHD transgenic mice

2016 ◽  
Vol 25 (9) ◽  
pp. 1780-1791 ◽  
Author(s):  
Susanna Mantovani ◽  
Richard Gordon ◽  
Rui Li ◽  
Daniel C. Christie ◽  
Vinod Kumar ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Motor Deficits ◽  
Striatal Degeneration

scholarly journals HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation

2014 ◽  
Vol 112 (1) ◽  
pp. E56-E64 ◽  
Author(s):  
Haiqun Jia ◽  
Charles D. Morris ◽  
Roy M. Williams ◽  
Jeanne F. Loring ◽  
Elizabeth A. Thomas
Keyword(s):  
Dna Methylation ◽  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Hdac Inhibitors ◽  
Hdac Inhibition ◽  
Transgenerational Effects ◽  
Treated Male ◽  
Disease Phenotypes ◽  
Cpg Sites

Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression and, in turn, influence resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, although their exact mechanisms of action are unclear. To identify mechanisms associated with HDAC inhibition, we performed microarray analysis on brain and muscle samples treated with the HDAC1/3-targeting inhibitor, HDACi 4b. Pathways analyses of microarray datasets implicate DNA methylation as significantly associated with HDAC inhibition. Further assessment of DNA methylation changes elicited by HDACi 4b in human fibroblasts from normal controls and patients with Huntington’s disease (HD) using the Infinium HumanMethylation450 BeadChip revealed a limited, but overlapping, subset of methylated CpG sites that were altered by HDAC inhibition in both normal and HD cells. Among the altered loci of Y chromosome-linked genes, KDM5D, which encodes Lys (K)-specific demethylase 5D, showed increased methylation at several CpG sites in both normal and HD cells, as well as in DNA isolated from sperm from drug-treated male mice. Further, we demonstrate that first filial generation (F1) offspring from drug-treated male HD transgenic mice show significantly improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice, in association with increased Kdm5d expression, and decreased histone H3 Lys4 (K4) (H3K4) methylation in the CNS of male offspring. Additionally, we show that overexpression of Kdm5d in mutant HD striatal cells significantly improves metabolic deficits. These findings indicate that HDAC inhibitors can elicit transgenerational effects, via cross-talk between different epigenetic mechanisms, to have an impact on disease phenotypes in a beneficial manner.

scholarly journals Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice

2004 ◽  
Vol 13 (15) ◽  
pp. 1599-1610 ◽  
Author(s):  
Gabriele Schilling ◽  
Alena V. Savonenko ◽  
Alexandra Klevytska ◽  
Johanna L. Morton ◽  
Stina M. Tucker ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Nuclear Targeting

Gene expression analysis on a single cell level in Purkinje cells of Huntington's disease transgenic mice

2012 ◽  
Vol 517 (1) ◽  
pp. 7-12 ◽  
Author(s):  
Philipp Euler ◽  
Bernd Friedrich ◽  
Ruhtraut Ziegler ◽  
Alexandre Kuhn ◽  
Katrin S. Lindenberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Huntington's Disease ◽  
Single Cell ◽  
Huntington’S Disease ◽  
Purkinje Cells ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Single Cell Level ◽  
Cell Level

scholarly journals Disruption of zinc transporter ZnT3 transcriptional activity and synaptic vesicular zinc in the brain of Huntington’s disease transgenic mouse

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Li Niu ◽  
Li Li ◽  
Shiming Yang ◽  
Weixi Wang ◽  
Cuifang Ye ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transcriptional Activity ◽  
Zinc Transporter ◽  
Zinc Homeostasis ◽  
Luciferase Reporter ◽  
Synaptic Dysfunction ◽  
Mutant Huntingtin ◽  
Luciferase Reporter Gene

Abstract Background Huntington’s disease (HD) is a neurodegenerative disease that involves a complex combination of psychiatric, cognitive and motor impairments. Synaptic dysfunction has been implicated in HD pathogenesis. However, the mechanisms have not been clearly delineated. Synaptic vesicular zinc is closely linked to modulating synaptic transmission and maintaining cognitive ability. It is significant to assess zinc homeostasis for further revealing the pathogenesis of synaptic dysfunction and cognitive impairment in HD. Results Histochemical staining by autometallography indicated that synaptic vesicular zinc was decreased in the hippocampus, cortex and striatum of N171-82Q HD transgenic mice. Analyses by immunohistochemistry, Western blot and RT-PCR found that the expression of zinc transporter 3 (ZnT3) required for transport of zinc into synaptic vesicles was obviously reduced in these three brain regions of the HD mice aged from 14 to 20 weeks  and  BHK  cells  expressing  mutant  huntingtin. Significantly, dual-luciferase reporter gene and chromatin immunoprecipitation assays demonstrated that transcription factor Sp1 could activate ZnT3 transcription via its binding to the GC boxes in ZnT3 promoter. Moreover, mutant huntingtin was found to inhibit the binding of Sp1 to the promoter of ZnT3 and down-regulate ZnT3 expression, and the decline in ZnT3 expression could be ameliorated through overexpression of Sp1. Conclusions This is first study to reveal a significant loss of synaptic vesicular zinc and a decline in ZnT3 transcriptional activity in the HD transgenic mice. Our work sheds a novel mechanistic insight into pathogenesis of HD that mutant huntingtin down-regulates expression of ZnT3 through inhibiting binding of Sp1 to the promoter of ZnT3 gene, causing disruption of synaptic vesicular zinc homeostasis. Disrupted vesicular zinc ultimately leads to early synaptic dysfunction and cognitive deficits in HD. It is also suggested that maintaining normal synaptic vesicular zinc concentration is a potential therapeutic strategy for HD.

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