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      The Huntington's Disease-Related Cardiomyopathy Prevents a Hypertrophic Response in the R6/2 Mouse Model

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          Abstract

          Huntington's disease (HD) is neurodegenerative disorder for which the mutation results in an extra-long tract of glutamines that causes the huntingtin protein to aggregate. It is characterized by neurological symptoms and brain pathology that is associated with nuclear and cytoplasmic aggregates and with transcriptional deregulation. Despite the fact that HD has been recognized principally as a neurological disease, there are multiple epidemiological studies showing that HD patients exhibit a high rate of cardiovascular events leading to heart failure. To unravel the mechanistic basis of cardiac dysfunction in HD, we employed a wide range of molecular techniques using the well-established genetic R6/2 mouse model that develop a considerable degree of the cardiac atrophy at end stage disease. We found that chronic treatment with isoproterenol, a potent beta-adrenoreceptor agonist, did not change the overall gross morphology of the HD murine hearts. However, there was a partial response to the beta-adrenergenic stimulation by the further re-expression of foetal genes. In addition we have profiled the expression level of Hdacs in the R6/2 murine hearts and found that the isoproterenol stimulation of Hdac expression was partially blocked. For the first time we established the Hdac transcriptional profile under hypertrophic conditions and found 10 out of 18 Hdacs to be markedly deregulated. Therefore, we conclude that R6/2 murine hearts are not able to respond to the chronic isoproterenol treatment to the same degree as wild type hearts and some of the hypertrophic signals are likely attenuated in the symptomatic HD animals.

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          Most cited references23

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          The hunt for huntingtin function: interaction partners tell many different stories.

          Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormally elongated polyglutamine (polyQ) tract in the large protein huntingtin (htt). Currently, both the normal function of htt in neurons and the molecular mechanism by which the expanded polyQ sequence in htt causes selective neurodegeneration remain elusive. Research in past years has identified several htt-interacting proteins such as htt-interacting protein 1, Src homology region 3-containing Grb2-like protein 3, protein kinase C and casein kinase substrate in neurons 1, htt-associated protein 1, postsynaptic density-95, FIP-2 (for 14.7K-interacting protein), specificity protein 1 and nuclear receptor co-repressor. These proteins play roles in clathrin-mediated endocytosis, apoptosis, vesicle transport, cell signalling, morphogenesis and transcriptional regulation, suggesting that htt is also involved in these processes.
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            Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development.

            The adult heart responds to stress signals by hypertrophic growth, which is often accompanied by activation of a fetal cardiac gene program and eventual cardiac demise. We showed previously that histone deacetylase 9 (HDAC9) acts as a suppressor of cardiac hypertrophy and that mice lacking HDAC9 are sensitized to cardiac stress signals. Here we report that mice lacking HDAC5 display a similar cardiac phenotype and develop profoundly enlarged hearts in response to pressure overload resulting from aortic constriction or constitutive cardiac activation of calcineurin, a transducer of cardiac stress signals. In contrast, mice lacking either HDAC5 or HDAC9 show a hypertrophic response to chronic beta-adrenergic stimulation identical to that of wild-type littermates, suggesting that these HDACs modulate a specific subset of cardiac stress response pathways. We also show that compound mutant mice lacking both HDAC5 and HDAC9 show a propensity for lethal ventricular septal defects and thin-walled myocardium. These findings reveal central roles for HDACs 5 and 9 in the suppression of a subset of cardiac stress signals as well as redundant functions in the control of cardiac development.
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              Huntington's disease gene (IT15) is widely expressed in human and rat tissues.

              Huntington's Disease (HD) is notable for selective neuronal vulnerability in the basal ganglia and cerebral cortex. We have investigated in human and rodent tissues the expression of the gene (IT15) whose mutation causes HD. IT15 is widely expressed, with highest levels of expression in brain, but also in lung, testis, ovary, and other tissues. Within the brain, expression is widespread with a neuronal pattern and is not enriched in the basal ganglia. Expression of IT15 is not reduced in the brain of HD patients when corrected for actin (though it is slightly decreased in the striatum when uncorrected, consistent with neuronal loss). Thus, the widespread distribution of IT15 expression does not correspond with the restricted distribution of neuropathologic changes in HD. We suggest that pathophysiology may relate to abnormal cell type-specific protein interactions of the HD protein.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                30 September 2014
                : 9
                : 9
                : e108961
                Affiliations
                [1]Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
                Emory University, United States of America
                Author notes

                Competing Interests: TM is an employee of Affimed Therapeutics AG. There are no patents, products in development, or marketed products to declare. The authors fully adhere to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                Conceived and designed the experiments: MM. Performed the experiments: MM MKB SAF LI TM. Analyzed the data: MM. Contributed reagents/materials/analysis tools: GPB. Wrote the paper: MM GPB.

                [¤]

                Current address: Affimed Therapeutics AG, Heidelberg, Germany

                Article
                PONE-D-14-36077
                10.1371/journal.pone.0108961
                4182603
                25268775
                e78f6ce8-71b9-4e24-b520-6cdb6e55265b
                Copyright @ 2014

                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.

                History
                : 11 August 2014
                : 5 September 2014
                Page count
                Pages: 10
                Funding
                This work was supported by the CHDI Foundation, a not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington's disease. Research conducted at King's College London was performed in collaboration with and funded by the CHDI Foundation. In these cases, the funder, through CHDI Management, fully participated in study design, data collection and analysis, the decision to publish, and preparation of the manuscript. TM is currently an employee of Affimed Therapeutics AG. Affimed Therapeutics AG provided no support for this work. They did not provide salary support for TM when he was working at King's College London and they did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the authors is articulated in the ‘author contributions’ section.
                Categories
                Research Article
                Biology and Life Sciences
                Genetics
                Genetics of Disease
                Genetic Disorders
                Molecular Biology
                Neuroscience
                Physiology
                Cardiovascular Physiology
                Medicine and Health Sciences
                Cardiology
                Cardiac Hypertrophy
                Heart Failure
                Neurology
                Neurodegenerative Diseases
                Huntington Disease
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are in the paper and its supporting information files.

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