{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:28:27Z","timestamp":1787005707539,"version":"build-2736575974"},"reference-count":69,"publisher":"National Academy of Sciences","issue":"1","license":[{"start":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T00:00:00Z","timestamp":1577059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,1,7]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Phosphodiesterase 10A (PDE10A) is as a target of interest in Huntington\u2019s disease (HD) as levels of the enzyme have been shown to decrease prior to the development of the hallmark motor symptoms. Clearly, a better understanding of how PDE10A protein levels change as HD develops is required. Here we show that mutations in the regulatory GAF domains of PDE10A that cause hyperkinetic syndromes in humans lead to misprocessing of the PDE10A enzyme that ultimately leads to targeted degradation by the ubiquitin proteasome system or clearance by autophagy. Both mechanisms result in a paucity of PDE10A activity that lead to a loss of movement coordination. Our research suggests that similar mechanisms may underpin PDE10A loss during HD.<\/jats:p>","DOI":"10.1073\/pnas.1916398117","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T20:36:45Z","timestamp":1577133405000},"page":"677-688","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme"],"prefix":"10.1073","volume":"117","author":[{"given":"Gonzalo S.","family":"Tejeda","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular and Medical Science, University of Glasgow, G12 8QQ Glasgow, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellanor L.","family":"Whiteley","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Science, University of Glasgow, G12 8QQ Glasgow, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek Z.","family":"Deeb","sequence":"additional","affiliation":[{"name":"AstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Tufts University School of Medicine, Boston, MA 02111;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland W.","family":"B\u00fcrli","sequence":"additional","affiliation":[{"name":"Neuroscience, IMED Biotech Unit, AstraZeneca, CB21 6GH Cambridge, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Moss","sequence":"additional","affiliation":[{"name":"AstraZeneca-Tufts University Laboratory for Basic and Translational Neuroscience Research, Tufts University School of Medicine, Boston, MA 02111;"},{"name":"Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eamonn","family":"Sheridan","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, University of Leeds, LS9 7TF Leeds, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Brandon","sequence":"additional","affiliation":[{"name":"Neuroscience, IMED Biotech Unit, AstraZeneca, Boston, MA 024515"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2469-6316","authenticated-orcid":false,"given":"George S.","family":"Baillie","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Science, University of Glasgow, G12 8QQ Glasgow, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,12,23]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-006-0510-4"},{"key":"e_1_3_3_2_2","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1111\/j.1471-4159.2010.06672.x","article-title":"Differential vulnerability of neurons in Huntington\u2019s disease: The role of cell type-specific features","volume":"113","author":"Han I.","year":"2010","unstructured":"I. Han, Y. You, J. H. Kordower, S. T. Brady, G. A. Morfini, Differential vulnerability of neurons in Huntington\u2019s disease: The role of cell type-specific features. J. Neurochem. 113, 1073\u20131091 (2010).","journal-title":"J. Neurochem."},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2004.03796.x"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000037"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2016.07.033"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv219"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv214"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002391"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2003.11.009"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.06.010"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.148"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2014.1954"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.03.015"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27175"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.02.015"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38507"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.27523"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.595769"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1635-10.2010"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(99)00171-7"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308471200"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-160195"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-160211"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1006551107"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.118.1.63"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221381398"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00121.2006"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C400302200"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/dneu.22534"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.306183"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2014.07.002"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM117.000117"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200507002"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-16-07027.2002"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200810098"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986708783330692"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.143.7.1883"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00939-5"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.5.1393"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-7-56"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.6705"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02264"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2014.09.003"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep27733"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-1004-0"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0854.2002.30602.x"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-58811-7_2"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2019.04.001"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800595200"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.354647"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.657668"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2009.06926.x"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2014.22"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3741"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201593594"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01434-12"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2019.02.007"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pep.2014.03.010"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2814"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.2122"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.146.6.1239"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep38681"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.01.020"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02998"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81782-1"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M310994200"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1066"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20819"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj1870381"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1916398117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,28]],"date-time":"2024-07-28T23:08:53Z","timestamp":1722208133000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1916398117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,23]]},"references-count":69,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1,7]]}},"alternative-id":["10.1073\/pnas.1916398117"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1916398117","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,23]]},"assertion":[{"value":"2019-12-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}