{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T03:20:33Z","timestamp":1789874433472,"version":"4.0.1"},"reference-count":85,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS098243"],"award-info":[{"award-number":["R01NS098243"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS100008"],"award-info":[{"award-number":["R01NS100008"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain Pathology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Accumulating evidence suggests X\u2010linked dominant mutations in <jats:italic>UBQLN2<\/jats:italic> cause amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) through both loss\u2010 and gain\u2010of\u2010function mechanisms. However, the mechanisms by which the mutations cause disease are still unclear. The goal of the study was to uncover the possible pathomechanism(s) by which <jats:italic>UBQLN2<\/jats:italic> mutations cause ALS\/FTD. An analysis of proteomic changes in neuronal tissue was used to identify proteins with altered accumulation in the P497S UBQLN2 transgenic mouse model of ALS\/FTD. We then used immunocytochemistry and biochemical techniques to confirm protein changes in the mutant P497S mice. Additionally, we used cell lines inactivated of UBQLN2 expression to determine whether its loss underlies the alteration in the proteins seen in P497S mice. The proteome screen identified a dramatic alteration of serine protease inhibitor (serpin) proteins in the mutant P497S animals. Double immunofluorescent staining of brain and spinal cord tissues of the mutant and control mice revealed an age\u2010dependent change in accumulation of Serpin A1, C1, and I1 in puncta whose staining colocalized with UBQLN2 puncta in the mutant P497S mice. Serpin A1 aggregation in P497S animals was confirmed by biochemical extraction and filter retardation assays. A similar phenomenon of serpin protein aggregation was found in HeLa and NSC34 motor neuron cells with inactivated UBQLN2 expression. We found aberrant aggregation of serpin proteins, particularly Serpin A1, in the brain and spinal cord of the P497S UBQLN2 mouse model of ALS\/FTD. Similar aggregation of serpin proteins was found in UBQLN2 knockout cells suggesting that serpin aggregation in the mutant P497S animals may stem from loss of UBQLN2 function. Because serpin aggregation is known to cause disease through both loss\u2010 and gain\u2010of\u2010function mechanisms, we speculate that their accumulation in the P497S mouse model of ALS\/FTD may contribute to disease pathogenesis through similar mechanism(s).<\/jats:p>","DOI":"10.1111\/bpa.12948","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T11:36:01Z","timestamp":1617017761000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Serpin neuropathology in the P497S UBQLN2 mouse model of ALS\/FTD"],"prefix":"10.1111","volume":"31","author":[{"given":"Nicole R.","family":"Higgins","sequence":"first","affiliation":[{"name":"Program in Molecular Medicine University of Maryland School of Medicine Baltimore MD USA"},{"name":"Center for Biomedical Engineering and Technology Department of Anatomy and Neurobiology University of Maryland School of Medicine Baltimore MD 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