{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:23:39Z","timestamp":1787894619231,"version":"build-2784847793"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T00:00:00Z","timestamp":1682467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"University of Antwerp Research Funds"},{"DOI":"10.13039\/501100004727","name":"Vlaams Instituut voor Biotechnologie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004727","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U19AG063911"],"award-info":[{"award-number":["U19AG063911"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UG3 NS103870"],"award-info":[{"award-number":["UG3 NS103870"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["74580"],"award-info":[{"award-number":["74580"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005930","name":"Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005930","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Holloway Postdoctoral fellowship"},{"DOI":"10.13039\/100003607","name":"Association for Frontotemporal Degeneration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003607","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers.<\/jats:p>\n                  <jats:p>Recently, cryo-electron microscopy studies showed that a C-terminal fragment (CTF) of TMEM106B (amino acid residues 120\u2013254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal ageing brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown.<\/jats:p>\n                  <jats:p>We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical analyses performed in the same study population.<\/jats:p>\n                  <jats:p>Immunoblot analysis showed the expected \u223c30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF, whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P &amp;lt; 0.001) and the presence of the TMEM106B risk haplotype (rs = 0.469, P &amp;lt; 0.001). Although there was a strong overall correlation between the results of immunoblot and immunohistochemistry (rs = 0.662, P &amp;lt; 0.001), 27 cases (37%) were found to have higher amounts of TMEM106B CTFs detected by immunohistochemistry, including most of the older individuals who were neuropathologically normal and individuals who carried two protective TMEM106B haplotypes.<\/jats:p>\n                  <jats:p>Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and immunohistochemistry in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications.<\/jats:p>","DOI":"10.1093\/brain\/awad133","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T18:52:04Z","timestamp":1682535124000},"page":"4055-4064","source":"Crossref","is-referenced-by-count":33,"title":["C-terminal TMEM106B fragments in human brain correlate with disease-associated\n                    <i>TMEM106B<\/i>\n                    haplotypes"],"prefix":"10.1093","volume":"146","author":[{"given":"Cristina","family":"T. Vicente","sequence":"first","affiliation":[{"name":"VIB Center for Molecular Neurology, University of Antwerp , 2610, Antwerp , Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp , 2610, Antwerp , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolien","family":"Perneel","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, University of Antwerp , 2610, Antwerp , Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp , 2610, Antwerp , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Wynants","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, University of Antwerp , 2610, Antwerp , Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp , 2610, Antwerp , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bavo","family":"Heeman","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, University of Antwerp , 2610, Antwerp , Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp , 2610, Antwerp , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marleen","family":"Van den Broeck","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, University of Antwerp , 2610, Antwerp , Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp , 2610, Antwerp , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32233 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Pathology, Vancouver Coastal Health , Vancouver, BC V5Z1M9 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"Faura","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, University of Antwerp , 2610, Antwerp , Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp , 2610, Antwerp , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian R A","family":"Mackenzie","sequence":"additional","affiliation":[{"name":"Department of Pathology, Vancouver Coastal Health , Vancouver, BC V5Z1M9 , Canada"},{"name":"Department of Pathology, University of British Columbia , Vancouver, BC V6T 1Z7 , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Rademakers","sequence":"additional","affiliation":[{"name":"VIB Center for Molecular Neurology, University of Antwerp , 2610, Antwerp , Belgium"},{"name":"Department of Biomedical Sciences, University of Antwerp , 2610, Antwerp , Belgium"},{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32233 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,26]]},"reference":[{"key":"2023100302120547400_awad133-B1","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1016\/j.cell.2022.02.026","article-title":"Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases","volume":"185","author":"Chang","year":"2022","journal-title":"Cell"},{"key":"2023100302120547400_awad133-B2","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41422-022-00665-3","article-title":"Generic amyloid fibrillation of TMEM106B in patient with Parkinson\u2019s disease dementia and normal elders","volume":"32","author":"Fan","year":"2022","journal-title":"Cell Res"},{"key":"2023100302120547400_awad133-B3","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/s41586-022-04670-9","article-title":"Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43","volume":"605","author":"Jiang","year":"2022","journal-title":"Nature"},{"key":"2023100302120547400_awad133-B4","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/s41586-022-04650-z","article-title":"Age-dependent formation of TMEM106B amyloid filaments in human brains","volume":"605","author":"Schweighauser","year":"2022","journal-title":"Nature"},{"key":"2023100302120547400_awad133-B5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev-biochem-061516-045115","article-title":"Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade","volume":"86","author":"Chiti","year":"2017","journal-title":"Annu Rev Biochem"},{"key":"2023100302120547400_awad133-B6","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40035-017-0077-5","article-title":"Protein misfolding in neurodegenerative diseases: implications and strategies","volume":"6","author":"Sweeney","year":"2017","journal-title":"Transl Neurodegener"},{"key":"2023100302120547400_awad133-B7","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1093\/hmg\/dds475","article-title":"The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function","volume":"22","author":"Brady","year":"2013","journal-title":"Hum Mol Genet"},{"key":"2023100302120547400_awad133-B8","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.mcn.2014.07.006","article-title":"Lysosome size, motility and stress response regulated by fronto-temporal dementia modifier TMEM106B","volume":"61","author":"Stagi","year":"2014","journal-title":"Mol Cell Neurosci"},{"key":"2023100302120547400_awad133-B9","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1038\/s41467-018-05013-x","article-title":"TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins","volume":"9","author":"Kundu","year":"2018","journal-title":"Nat Commun"},{"key":"2023100302120547400_awad133-B10","doi-asserted-by":"crossref","first-page":"3506","DOI":"10.1016\/j.celrep.2020.02.060","article-title":"The FTLD risk factor TMEM106B regulates the transport of lysosomes at the axon initial segment of motoneurons","volume":"30","author":"L\u00fcningschr\u00f6r","year":"2020","journal-title":"Cell Rep"},{"key":"2023100302120547400_awad133-B11","doi-asserted-by":"crossref","first-page":"19355","DOI":"10.1074\/jbc.M112.365098","article-title":"Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), 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Neuropathol"},{"key":"2023100302120547400_awad133-B21","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s00401-013-1239-x","article-title":"TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions","volume":"127","author":"Gallagher","year":"2014","journal-title":"Acta Neuropathol"},{"key":"2023100302120547400_awad133-B22","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.cels.2017.02.009","article-title":"Differential aging analysis in human cerebral cortex identifies variants in TMEM106B and GRN that regulate aging phenotypes","volume":"4","author":"Rhinn","year":"2017","journal-title":"Cell Syst"},{"key":"2023100302120547400_awad133-B23","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s00401-019-02066-0","article-title":"The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal 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