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HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration
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نویسنده
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mielcarek m. ,landles c. ,weiss a. ,bradaia a. ,seredenina t. ,inuabasi l. ,osborne g.f. ,wadel k. ,touller c. ,butler r. ,robertson j. ,franklin s.a. ,smith d.l. ,park l. ,marks p.a. ,wanker e.e. ,olson e.n. ,luthi-carter r. ,van der putten h. ,beaumont v. ,bates g.p.
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منبع
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plos biology - 2013 - دوره : 11 - شماره : 11
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چکیده
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Histone deacetylase (hdac) 4 is a transcriptional repressor that contains a glutamine-rich domain. we hypothesised that it may be involved in the molecular pathogenesis of huntington's disease (hd),a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. we found that hdac4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. we show that hdac4 reduction delayed cytoplasmic aggregate formation,restored bdnf transcript levels,and rescued neuronal and cortico-striatal synaptic function in hd mouse models. this was accompanied by an improvement in motor coordination,neurological phenotypes,and increased lifespan. surprisingly,hdac4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of hd. hdac4 reduction presents a novel strategy for targeting huntingtin aggregation,which may be amenable to small-molecule therapeutics. © 2013 mielcarek et al.
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آدرس
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department of medical and molecular genetics,king's college london,london, United Kingdom, department of medical and molecular genetics,king's college london,london, United Kingdom, novartis institutes for biomedical research,neuroscience discovery,basel, Switzerland, neuroservice,aix en provence, France, brain mind institute,ecole polytechnique federale de lausanne,lausanne, Switzerland, department of medical and molecular genetics,king's college london,london, United Kingdom, department of medical and molecular genetics,king's college london,london, United Kingdom, neuroservice,aix en provence, France, neuroservice,aix en provence, France, department of medical and molecular genetics,king's college london,london,united kingdom,nuffield laboratory of ophthalmology,university of oxford,the john radcliffe hospital,oxford, United Kingdom, department of medical and molecular genetics,king's college london,london, United Kingdom, department of medical and molecular genetics,king's college london,london, United Kingdom, department of medical and molecular genetics,king's college london,london, United Kingdom, chdi management inc./chdi foundation,los angeles,ca, United States, cell biology program,memorial sloan-kettering cancer center,new york,ny, United States, neuroproteomics,max delbrueck center for molecular medicine,berlin, Germany, department of molecular biology,southwestern university,dallas,tx, United States, brain mind institute,ecole polytechnique federale de lausanne,lausanne, Switzerland, novartis institutes for biomedical research,neuroscience discovery,basel, Switzerland, chdi management inc./chdi foundation,los angeles,ca, United States, department of medical and molecular genetics,king's college london,london, United Kingdom
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Authors
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