{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T01:58:01Z","timestamp":1773712681870,"version":"3.50.1"},"reference-count":25,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Private funds at University of Cincinnati and University of Toronto","award":["none"],"award-info":[{"award-number":["none"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia\u2013ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann\u2013Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.<\/jats:p>","DOI":"10.3390\/ijms22147292","type":"journal-article","created":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T12:31:25Z","timestamp":1625661085000},"page":"7292","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6438-9911","authenticated-orcid":false,"given":"Luca","family":"Marsili","sequence":"first","affiliation":[{"name":"Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Sharma","sequence":"additional","affiliation":[{"name":"Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto J.","family":"Espay","sequence":"additional","affiliation":[{"name":"Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0851-2903","authenticated-orcid":false,"given":"Alice","family":"Migazzi","sequence":"additional","affiliation":[{"name":"Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology\u2014CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7979-0065","authenticated-orcid":false,"given":"Elhusseini","family":"Abdelghany","sequence":"additional","affiliation":[{"name":"Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily J.","family":"Hill","sequence":"additional","affiliation":[{"name":"Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5981-3140","authenticated-orcid":false,"given":"Kevin R.","family":"Duque","sequence":"additional","affiliation":[{"name":"Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew C.","family":"Hagen","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4727-192X","authenticated-orcid":false,"given":"Christopher D.","family":"Stephen","sequence":"additional","affiliation":[{"name":"Ataxia Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-5511","authenticated-orcid":false,"given":"Gabor G.","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Disease (CRND), Department of Laboratory Medicine and Pathobiology, University of Toronto, 60 Leonard Ave, Krembil Discovery Tower, Toronto, ON M5T 0S8, Canada"},{"name":"Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON M5T 1M8, Canada"},{"name":"Edmond J. Safra Program in Parkinson\u2019s Disease, Rossy Progressive Supranuclear Palsy Program and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto, ON M5T 2S8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony E.","family":"Lang","sequence":"additional","affiliation":[{"name":"Edmond J. Safra Program in Parkinson\u2019s Disease, Rossy Progressive Supranuclear Palsy Program and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto, ON M5T 2S8, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2542-8954","authenticated-orcid":false,"given":"Marios","family":"Hadjivassiliou","sequence":"additional","affiliation":[{"name":"Academic Department of Neurosciences, Royal Hallamshire Hospital, University of Sheffield, Sheffield S10 2JF, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Basso","sequence":"additional","affiliation":[{"name":"Laboratory of Transcriptional Neurobiology, Department of Cellular, Computational and Integrative Biology\u2014CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcelo A.","family":"Kauffman","sequence":"additional","affiliation":[{"name":"Consultorio y Laboratorio de Neurogen\u00e9tica, Centro Universitario de Neurolog\u00eda Jos\u00e9 Mar\u00eda Ramos Mej\u00eda, Buenos Aires C1221ADC, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Sturchio","sequence":"additional","affiliation":[{"name":"Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.neuron.2013.01.036","article-title":"Transglutaminase and polyamination of tubulin: Posttranslational modification for stabilizing axonal microtubules","volume":"78","author":"Song","year":"2013","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00726-011-1209-3","article-title":"\u03b3-Glutamylamines and neurodegenerative diseases","volume":"44","author":"Jeitner","year":"2013","journal-title":"Amino Acids"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/j.1471-4159.2009.05843.x","article-title":"Transglutaminases and neurodegeneration","volume":"109","author":"Jeitner","year":"2009","journal-title":"J. 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