{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T11:57:11Z","timestamp":1779364631957,"version":"3.53.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder, caused by a CAG expansion in the atrophin-1 gene. The clinical features include chorea, ataxia, incoordination, emotional changes and dementia, progressing to early mortality. The atrophin-1 protein sequence contains a putative N-terminal nuclear localization signal (NLS) and a putative C-terminal nuclear export signal (NES). To investigate whether nuclear localization of atrophin-1 plays a role in the pathogenesis of DRPLA, we designed alterations of the NLS and NES by site-directed mutagenesis. We generated transgenic mice expressing mutant full-length atrophin-1 (repeat length\u2009=\u200965) with alteration of either the nuclear export signal (At65QmNES, predicted to result in a higher ratio of nuclear to cytosolic atrophin-1 than in control), or the nuclear localization signal (At65QmNLS, predicated to retain more cytosolic atrophin-1), respectively. With equivalent levels of atrophin-1 expression, At65QmNES mice displayed more nuclear accumulation of atrophin-1 and its fragments than At65QmNLS or control mice expressing endogenous normal Atrophin-1. Moreover, At65QmNES mice had a shorter life span and more severe locomotor defects than did At65QmNLS (and non-transgenic control) mice. Additionally, we found that At65QmNES caused more pathology in mouse brains than did At65QmNLS. These results provide evidence that nuclear localization enhances the phenotype of mutant atrophin-1-linked neuropathology. In addition, our findings indicate that the AT65QmNES transgenic mouse will be a valuable model for future studies of DRPLA pathogenesis and potential therapeutics.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf048","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T04:38:13Z","timestamp":1745383093000},"page":"1017-1025","source":"Crossref","is-referenced-by-count":2,"title":["The nuclear export signal mediates mutant atrophin-1-induced neuropathology in a mouse model of DRPLA"],"prefix":"10.1093","volume":"34","author":[{"given":"Yideng","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Fuehrer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick C","family":"Nucifora","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Margolis","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]},{"name":"Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanli W","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, MD 21287 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"2025060505165346100_ref1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/1523-1747.ep12500082","article-title":"The pathogenic mechanisms of blister formation in bullous pemphigoid","volume":"79","author":"Naito","year":"1982","journal-title":"J Invest 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