000199183 001__ 199183
000199183 005__ 20190316235920.0
000199183 0247_ $$2doi$$a10.1371/journal.pbio.1001717
000199183 022__ $$a1545-7885
000199183 02470 $$2ISI$$a000330352200019
000199183 037__ $$aARTICLE
000199183 245__ $$aHDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration
000199183 260__ $$bPublic Library Science$$c2013$$aSan Francisco
000199183 269__ $$a2013
000199183 300__ $$a16
000199183 336__ $$aJournal Articles
000199183 520__ $$aHistone 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.
000199183 700__ $$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England$$aMielcarek, Michal
000199183 700__ $$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England$$aLandles, Christian
000199183 700__ $$uNovartis Inst BioMed Res, Basel, Switzerland$$aWeiss, Andreas
000199183 700__ $$uNeuroserv, Aix En Provence, France$$aBradaia, Amyaouch
000199183 700__ $$uEcole Polytech Fed Lausanne, Brain Mind Inst, Lausanne, Switzerland$$aSeredenina, Tamara
000199183 700__ $$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England$$aInuabasi, Linda
000199183 700__ $$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England$$aOsborne, Georgina F.
000199183 700__ $$uNeuroserv, Aix En Provence, France$$aWadel, Kristian
000199183 700__ $$uNeuroserv, Aix En Provence, France$$aTouller, Chrystelle
000199183 700__ $$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England$$aButler, Rachel
000199183 700__ $$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England$$aRobertson, Janette
000199183 700__ $$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England$$aFranklin, Sophie A.
000199183 700__ $$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England$$aSmith, Donna L.
000199183 700__ $$uCHDI Fdn, CHDI Management Inc, Los Angeles, CA USA$$aPark, Larry
000199183 700__ $$uMem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA$$aMarks, Paul A.
000199183 700__ $$uMax Delbruck Ctr Mol Med, Berlin, Germany$$aWanker, Erich E.
000199183 700__ $$aOlson, Eric N.
000199183 700__ $$0240509$$g158211$$uEcole Polytech Fed Lausanne, Brain Mind Inst, Lausanne, Switzerland$$aLuthi-Carter, Ruth
000199183 700__ $$aVan Der Putten, Herman
000199183 700__ $$uCHDI Fdn, CHDI Management Inc, Los Angeles, CA USA$$aBeaumont, Vahri
000199183 700__ $$aBates, Gillian P.$$uKings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England
000199183 773__ $$j11$$tPlos Biology$$k11$$qe1001717
000199183 8564_ $$uhttps://infoscience.epfl.ch/record/199183/files/journal.pbio.1001717.pdf$$zPublisher's version$$s3961541$$yPublisher's version
000199183 909C0 $$xU10838$$0252338$$pLNGF
000199183 909CO $$qGLOBAL_SET$$particle$$ooai:infoscience.tind.io:199183
000199183 917Z8 $$x182396
000199183 937__ $$aEPFL-ARTICLE-199183
000199183 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000199183 980__ $$aARTICLE