{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:58:25Z","timestamp":1790517505662,"version":"4.1.0"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"47","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2016,11,22]]},"abstract":"<jats:p>\n                    Missense mutations in\n                    <jats:italic>ubiquilin 2<\/jats:italic>\n                    (\n                    <jats:italic>UBQLN2<\/jats:italic>\n                    ) cause ALS with frontotemporal dementia (ALS\u2013FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying\n                    <jats:italic>UBQLN2<\/jats:italic>\n                    mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS\u2013FTD-linked P497S or P506T\n                    <jats:italic>UBQLN2<\/jats:italic>\n                    mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin\n                    <jats:sup>+<\/jats:sup>\n                    inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT\n                    <jats:italic>UBQLN2<\/jats:italic>\n                    were mostly devoid of clinical and pathological signs of disease. These\n                    <jats:italic>UBQLN2<\/jats:italic>\n                    mouse models provide valuable tools for identifying the mechanisms underlying ALS\u2013FTD pathogenesis and for investigating therapeutic strategies to halt disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1608432113","type":"journal-article","created":{"date-parts":[[2016,11,10]],"date-time":"2016-11-10T09:10:31Z","timestamp":1478769031000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":89,"title":["Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS\u2013FTD-linked\n                    <i>UBQLN2<\/i>\n                    mutations"],"prefix":"10.1073","volume":"113","author":[{"given":"Nhat T. T.","family":"Le","sequence":"first","affiliation":[{"name":"Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201;"},{"name":"Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201;"},{"name":"Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Kovlyagina","sequence":"additional","affiliation":[{"name":"Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 21201;"},{"name":"Department of Anatomy and Neurobiology, University of Maryland School of 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D.","family":"Kvarta","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam M.","family":"Van Dyke","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara A.","family":"LeGates","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Philips","sequence":"additional","affiliation":[{"name":"Brain Science Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"},{"name":"Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 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