{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T23:17:56Z","timestamp":1789341476835,"version":"build-2803163510"},"reference-count":63,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,12,19]],"date-time":"2023-12-19T00:00:00Z","timestamp":1702944000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009193","name":"Marsden Fund","doi-asserted-by":"publisher","award":["15\u2010UOA\u2010157"],"award-info":[{"award-number":["15\u2010UOA\u2010157"]}],"id":[{"id":"10.13039\/501100009193","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001509","name":"Royal Society Te Ap\u0101rangi","doi-asserted-by":"publisher","award":["15\u2010UOA\u2010003"],"award-info":[{"award-number":["15\u2010UOA\u2010003"]}],"id":[{"id":"10.13039\/501100001509","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain Pathology"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in the <jats:italic>UBQLN2<\/jats:italic> gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such <jats:italic>UBQLN2<\/jats:italic>\u2010linked cases of ALS\/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA\u2010binding protein of 43\u2009kDa (TDP\u201043). ALS and FTD without <jats:italic>UBQLN2<\/jats:italic> mutations are also characterised by TDP\u201043 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP\u201043 and ubiquilin 2 to disease pathogenesis remain largely under\u2010characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three <jats:italic>UBQLN2<\/jats:italic> p.T487I\u2010linked ALS\/FTD cases, three non\u2010<jats:italic>UBQLN2<\/jats:italic>\u2010linked (sporadic) ALS cases, and 8 non\u2010neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP\u201043 aggregates and aggregates containing both proteins in regions of interest to determine how <jats:italic>UBQLN2<\/jats:italic>\u2010linked and non\u2010<jats:italic>UBQLN2<\/jats:italic>\u2010linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP\u201043 are predominantly small and punctate and are abundant in the hippocampal formation, spinal cord, all tested regions of neocortex, medulla and substantia nigra in <jats:italic>UBQLN2<\/jats:italic>\u2010linked ALS\/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to <jats:italic>UBQLN2<\/jats:italic>\u2010linked ALS\/FTD. Overall, ubiquilin 2 is mainly deposited in clinically unaffected regions throughout the CNS such that symptomology in <jats:italic>UBQLN2<\/jats:italic>\u2010linked cases maps best to the aggregation of TDP\u201043.<\/jats:p>","DOI":"10.1111\/bpa.13230","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T06:14:05Z","timestamp":1703052845000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Distribution of ubiquilin 2 and <scp>TDP<\/scp>\u201043 aggregates throughout the <scp>CNS<\/scp> in <scp><i>UBQLN2<\/i><\/scp> p.<scp>T487I<\/scp>\u2010linked amyotrophic lateral sclerosis and frontotemporal dementia"],"prefix":"10.1111","volume":"34","author":[{"given":"Laura R.","family":"Nementzik","sequence":"first","affiliation":[{"name":"School of Biological Sciences University of Auckland  Auckland New Zealand"},{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyrah M.","family":"Thumbadoo","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland  Auckland New Zealand"},{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen C.","family":"Murray","sequence":"additional","affiliation":[{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"},{"name":"Department of Anatomy and Medical Imaging University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gordon","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland  Auckland New Zealand"},{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Yang","sequence":"additional","affiliation":[{"name":"Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health, and Human Sciences Macquarie University  North Ryde New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian P.","family":"Blair","sequence":"additional","affiliation":[{"name":"Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health, and Human Sciences Macquarie University  North Ryde New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2138-7633","authenticated-orcid":false,"given":"Clinton","family":"Turner","sequence":"additional","affiliation":[{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"},{"name":"Department of Anatomy and Medical Imaging University of Auckland  Auckland New Zealand"},{"name":"Department of Anatomical Pathology, LabPlus Auckland City Hospital  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L. M.","family":"Faull","sequence":"additional","affiliation":[{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"},{"name":"Department of Anatomy and Medical Imaging University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice A.","family":"Curtis","sequence":"additional","affiliation":[{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"},{"name":"Department of Anatomy and Medical Imaging University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catriona","family":"McLean","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology Alfred Health  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garth A.","family":"Nicholson","sequence":"additional","affiliation":[{"name":"Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health, and Human Sciences Macquarie University  North Ryde New South Wales Australia"},{"name":"Northcott Neuroscience Laboratory ANZAC Research Institute  Sydney Australia"},{"name":"Molecular Medicine Laboratory Concord Repatriation General Hospital  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly E. V.","family":"Swanson","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland  Auckland New Zealand"},{"name":"Centre for Brain Research University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4064-3599","authenticated-orcid":false,"given":"Emma L.","family":"Scotter","sequence":"additional","affiliation":[{"name":"School of Biological Sciences University of Auckland  Auckland New Zealand"},{"name":"Centre for Brain Research University of Auckland  Auckland New 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