Validation of HDAC6 and SIRT2 tubulin deacetylases as therapeutic targets for Huntington's disease

Since the identification of a widespread transcriptional dysregulation that occurs in Huntington's disease (HD), histone deacetylase (HDAC) inhibition has been explored as a possible therapeutic strategy for this devastating disease. Studies using broadrange acting HDAC inhibitors have shown gr...

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Main Author: Bobrowska, Anna
Published: King's College London (University of London) 2012
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Online Access:http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628114
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spelling ndltd-bl.uk-oai-ethos.bl.uk-6281142015-11-03T03:54:52ZValidation of HDAC6 and SIRT2 tubulin deacetylases as therapeutic targets for Huntington's diseaseBobrowska, Anna2012Since the identification of a widespread transcriptional dysregulation that occurs in Huntington's disease (HD), histone deacetylase (HDAC) inhibition has been explored as a possible therapeutic strategy for this devastating disease. Studies using broadrange acting HDAC inhibitors have shown great promise in HD mouse models. Concomitantly, effects of inhibition of individual HDACs have been investigated, however, these experiments have been most frequently performed in worm, fly, and cell and less so in mouse models of HD. Previous reports have demonstrated disease modifying potential for both HDAC6 and SIRT2, which are the only tubulin deacetylases known in mammals. Nevertheless, the therapeutic value of these enzymes has not yet been explored in a complex mammalian system. This work addressed the question of what is the effect of genetically depleting either HDAC6 or SIRT2 in the R6/2 mouse model of HD on disease progression. After thorough characterisation of both Hdac6KO and Sirt2KO mice and expression of either mutation in the R6/2 mouse, a battery of physiological, behavioural and molecular readouts has clearly demonstrated that previous studies performed in invertebrate or cell culture systems do not translate to the mouse and that, therefore, HDAC6 and SIRT2 inhibition would not be of therapeutic value and should not be prioritised as a therapeutic strategy in HD.616.85King's College London (University of London)http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628114https://kclpure.kcl.ac.uk/portal/en/theses/validation-of-hdac6-and-sirt2-tubulin-deacetylases-as-therapeutic-targets-for-huntingtons-disease(be8927be-820e-4e72-be61-ef5928102c79).htmlElectronic Thesis or Dissertation
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topic 616.85
spellingShingle 616.85
Bobrowska, Anna
Validation of HDAC6 and SIRT2 tubulin deacetylases as therapeutic targets for Huntington's disease
description Since the identification of a widespread transcriptional dysregulation that occurs in Huntington's disease (HD), histone deacetylase (HDAC) inhibition has been explored as a possible therapeutic strategy for this devastating disease. Studies using broadrange acting HDAC inhibitors have shown great promise in HD mouse models. Concomitantly, effects of inhibition of individual HDACs have been investigated, however, these experiments have been most frequently performed in worm, fly, and cell and less so in mouse models of HD. Previous reports have demonstrated disease modifying potential for both HDAC6 and SIRT2, which are the only tubulin deacetylases known in mammals. Nevertheless, the therapeutic value of these enzymes has not yet been explored in a complex mammalian system. This work addressed the question of what is the effect of genetically depleting either HDAC6 or SIRT2 in the R6/2 mouse model of HD on disease progression. After thorough characterisation of both Hdac6KO and Sirt2KO mice and expression of either mutation in the R6/2 mouse, a battery of physiological, behavioural and molecular readouts has clearly demonstrated that previous studies performed in invertebrate or cell culture systems do not translate to the mouse and that, therefore, HDAC6 and SIRT2 inhibition would not be of therapeutic value and should not be prioritised as a therapeutic strategy in HD.
author Bobrowska, Anna
author_facet Bobrowska, Anna
author_sort Bobrowska, Anna
title Validation of HDAC6 and SIRT2 tubulin deacetylases as therapeutic targets for Huntington's disease
title_short Validation of HDAC6 and SIRT2 tubulin deacetylases as therapeutic targets for Huntington's disease
title_full Validation of HDAC6 and SIRT2 tubulin deacetylases as therapeutic targets for Huntington's disease
title_fullStr Validation of HDAC6 and SIRT2 tubulin deacetylases as therapeutic targets for Huntington's disease
title_full_unstemmed Validation of HDAC6 and SIRT2 tubulin deacetylases as therapeutic targets for Huntington's disease
title_sort validation of hdac6 and sirt2 tubulin deacetylases as therapeutic targets for huntington's disease
publisher King's College London (University of London)
publishDate 2012
url http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628114
work_keys_str_mv AT bobrowskaanna validationofhdac6andsirt2tubulindeacetylasesastherapeutictargetsforhuntingtonsdisease
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