{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T10:31:51Z","timestamp":1793788311955,"version":"4.6.1"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T00:00:00Z","timestamp":1709769600000},"content-version":"vor","delay-in-days":35,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Transmembrane protein 106B (TMEM106B), previously identified as a risk factor in frontotemporal lobar degeneration, has recently been detected to form fibrillar aggregates in the brains of patients with various neurodegenerative diseases (NDs) and normal elders. While the specifics of when and where TMEM106B fibrils accumulate in human brains, as well as their connection to aging and disease progression, remain poorly understood. Here, we identified an antibody (NBP1-91311) that directly binds to TMEM106B fibrils extracted from the brain in vitro and to Thioflavin S-positive TMEM106B fibrillar aggregates in brain sections. We discovered that TMEM106B fibrils deposit in the human brain in an age-dependent manner. Notably, the TMEM106B fibril load in the brains of Parkinson\u2019s disease with dementia patients was significantly higher than in age-matched elders. Additionally, we found that TMEM106B fibrils predominantly accumulate in astrocytes and neurons and do not co-localize with the pathological deposition formed by other amyloid proteins such as \u03b1-synuclein, A\u03b2, and Tau. Our work provides a comprehensive analysis of the burden and cellular distribution of TMEM106B fibrils in human brains, underscoring the impact of both aging and disease conditions on TMEM106B fibril deposition. This highlights the potential significance of TMEM106B fibrils in various age-related NDs.<\/jats:p>","DOI":"10.1093\/lifemedi\/lnae011","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T17:47:36Z","timestamp":1709833656000},"source":"Crossref","is-referenced-by-count":9,"title":["Tracing TMEM106B fibril deposition in aging and Parkinson\u2019s disease with dementia brains"],"prefix":"10.1093","volume":"3","author":[{"given":"Wanbing","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University , Shanghai 200040 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University , Shanghai 200040 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinyue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University , Shanghai 200030 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University , Shanghai 200040 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University , Shanghai 200040 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University , Shanghai 200040 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wensheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histoembryology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University , Shanghai 200030 , China"},{"name":"Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University , Shanghai 200240 , China"},{"name":"WLA Laboratories, World Laureates Association , Shanghai 201203 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Liu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , Shanghai 201210 , China"},{"name":"State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University , Shanghai 200040 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"key":"2024052508553119800_CIT0001","first-page":"19355","article-title":"Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration","volume-title":"J Biol Chem","author":"Lang","year":"2012"},{"key":"2024052508553119800_CIT0002","first-page":"685","article-title":"The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function","volume-title":"Hum Mol Genet","author":"Brady","year":"2013"},{"key":"2024052508553119800_CIT0003","first-page":"450","article-title":"The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes","volume-title":"EMBO J","author":"Schwenk","year":"2014"},{"key":"2024052508553119800_CIT0004","first-page":"234","article-title":"Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions","volume-title":"Nat Genet","author":"Van Deerlin","year":"2010"},{"key":"2024052508553119800_CIT0005","first-page":"467","article-title":"TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers","volume-title":"Neurology","author":"Finch","year":"2011"},{"key":"2024052508553119800_CIT0006","first-page":"801","article-title":"TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia","volume-title":"Ann Neurol","author":"Tropea","year":"2019"},{"key":"2024052508553119800_CIT0007","first-page":"407","article-title":"TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions","volume-title":"Acta Neuropathol","author":"Gallagher","year":"2014"},{"key":"2024052508553119800_CIT0008","first-page":"581","article-title":"Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels","volume-title":"Arch Neurol","author":"Cruchaga","year":"2011"},{"key":"2024052508553119800_CIT0009","first-page":"267","article-title":"A novel temporal-predominant neuro-astroglial tauopathy associated with TMEM106B gene polymorphism in FTLD\/ALS-TDP","volume-title":"Brain Pathol","author":"Llibre-Guerra","year":"2021"},{"key":"2024052508553119800_CIT0010","first-page":"11","article-title":"rs1990622 variant associates with Alzheimer\u2019s disease and regulates TMEM106B expression in human brain tissues","volume-title":"BMC Med","author":"Hu","year":"2021"},{"key":"2024052508553119800_CIT0011","first-page":"108","article-title":"A novel Alzheimer disease locus located near the gene encoding tau protein","volume-title":"Mol Psychiatry","author":"Jun","year":"2016"},{"key":"2024052508553119800_CIT0012","first-page":"717","article-title":"TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease","volume-title":"Neurology","author":"Rutherford","year":"2012"},{"key":"2024052508553119800_CIT0013","first-page":"1628","article-title":"TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer\u2019s disease biomarker levels","volume-title":"Alzheimer's Dement","author":"Hong","year":"2021"},{"key":"2024052508553119800_CIT0014","first-page":"629","article-title":"TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy","volume-title":"Acta Neuropathol","author":"Mao","year":"2021"},{"key":"2024052508553119800_CIT0015","first-page":"373","article-title":"Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis","volume-title":"Acta Neuropathol","author":"Vass","year":"2011"},{"key":"2024052508553119800_CIT0016","first-page":"9276","article-title":"TMEM106B acts as a modifier of cognitive and motor functions in amyotrophic lateral sclerosis","volume-title":"Int J Mol Sci","author":"Manini","year":"2022"},{"key":"2024052508553119800_CIT0017","first-page":"503","article-title":"TMEM106B influences volume of left-sided temporal lobe and interhemispheric structures in the general population","volume-title":"Biol Psychiatry","author":"Adams","year":"2014"},{"key":"2024052508553119800_CIT0018","first-page":"45","article-title":"The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion","volume-title":"Acta Neuropathol","author":"Li","year":"2020"},{"key":"2024052508553119800_CIT0019","first-page":"404","article-title":"Differential aging analysis in human cerebral cortex identifies variants in TMEM106B and GRN that regulate aging phenotypes","volume-title":"Cell systems","author":"Rhinn","year":"2017"},{"key":"2024052508553119800_CIT0020","first-page":"239","article-title":"Neuropathological stageing of Alzheimer-related changes","volume-title":"Acta Neuropathol","author":"Braak","year":"1991"},{"key":"2024052508553119800_CIT0021","first-page":"167","article-title":"Cryo-EM structures of amyloid-\u03b2 42 filaments from human brains","volume-title":"Science","author":"Yang","year":"2022"},{"key":"2024052508553119800_CIT0022","first-page":"185","article-title":"Cryo-EM structures of tau filaments from Alzheimer\u2019s disease","volume-title":"Nature","author":"Fitzpatrick","year":"2017"},{"key":"2024052508553119800_CIT0023","first-page":"197","article-title":"Staging of brain pathology related to sporadic Parkinson\u2019s disease","volume-title":"Neurobiol Aging","author":"Braak","year":"2003"},{"key":"2024052508553119800_CIT0024","first-page":"128","article-title":"Characterisation of isolated alpha-synuclein filaments from substantia nigra of Parkinson\u2019s disease brain","volume-title":"Neurosci Lett","author":"Crowther","year":"2000"},{"key":"2024052508553119800_CIT0025","first-page":"791","article-title":"Structures of \u03b1-synuclein filaments from human brains with Lewy pathology","volume-title":"Nature","author":"Yang","year":"2022"},{"key":"2024052508553119800_CIT0026","first-page":"130","article-title":"Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis","volume-title":"Science","author":"Neumann","year":"2006"},{"key":"2024052508553119800_CIT0027","first-page":"139","article-title":"Structure of pathological TDP-43 filaments from ALS with FTLD","volume-title":"Nature","author":"Arseni","year":"2022"},{"key":"2024052508553119800_CIT0028","first-page":"898","article-title":"TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP","volume-title":"Nature","author":"Arseni","year":"2023"},{"key":"2024052508553119800_CIT0029","first-page":"523","article-title":"Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases","volume-title":"Nat Rev Neurosci","author":"Li","year":"2022"},{"key":"2024052508553119800_CIT0030","first-page":"65","article-title":"Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration","volume-title":"Acta Neuropathol","author":"Lee","year":"2017"},{"key":"2024052508553119800_CIT0031","first-page":"73","article-title":"Evidence of distinct \u03b1-synuclein strains underlying disease heterogeneity","volume-title":"Acta Neuropathol","author":"Holec","year":"2021"},{"key":"2024052508553119800_CIT0032","first-page":"e333","article-title":"Protein amyloid aggregate: Structure and 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TDP-43","volume-title":"Nature","author":"Jiang","year":"2022"},{"key":"2024052508553119800_CIT0037","first-page":"1346","article-title":"Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases","volume-title":"Cell","author":"Chang","year":"2022"},{"key":"2024052508553119800_CIT0038","first-page":"1669","article-title":"The comparative biology of neuromelanin and lipofuscin in the human brain","volume-title":"Cell Mol Life Sci","author":"Double","year":"2008"},{"key":"2024052508553119800_CIT0039","first-page":"487","article-title":"The molecular pathology of Alzheimer\u2019s disease","volume-title":"Neuron","author":"Selkoe","year":"1991"},{"key":"2024052508553119800_CIT0040","first-page":"2048","article-title":"Amidation of beta-amyloid peptide strongly reduced the amyloidogenic activity without alteration of the neurotoxicity","volume-title":"J 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pathol","author":"Hokkanen","year":"2020"},{"key":"2024052508553119800_CIT0045","first-page":"1503","article-title":"Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report","volume-title":"Brain","author":"Nelson","year":"2019"},{"key":"2024052508553119800_CIT0046","first-page":"e50197","article-title":"Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin-deficient mice","volume-title":"EMBO Rep","author":"Zhou","year":"2020"},{"key":"2024052508553119800_CIT0047","first-page":"e50241","article-title":"Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice","volume-title":"EMBO Rep","author":"Werner","year":"2020"},{"key":"2024052508553119800_CIT0048","first-page":"e50219","article-title":"Loss of TMEM106B and PGRN leads to severe lysosomal abnormalities and neurodegeneration in mice","volume-title":"EMBO Rep","author":"Feng","year":"2020"},{"key":"2024052508553119800_CIT0049","first-page":"281","article-title":"Loss of TMEM106B ameliorates lysosomal and frontotemporal dementia-related phenotypes in progranulin-deficient mice","volume-title":"Neuron","author":"Klein","year":"2017"},{"key":"2024052508553119800_CIT0050","first-page":"285","article-title":"Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging","volume-title":"Acta Neuropathol","author":"Perneel","year":"2023"},{"key":"2024052508553119800_CIT0051","first-page":"4055","article-title":"C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes","volume-title":"Brain.","author":"Vicente","year":"2023"},{"key":"2024052508553119800_CIT0052","first-page":"163","article-title":"Limbic-predominant age-related TDP-43 proteinopathy (LATE-NC) is associated with abundant TMEM106B pathology","volume-title":"Acta Neuropathol","author":"Neumann","year":"2023"},{"key":"2024052508553119800_CIT0053","first-page":"3374","article-title":"Propagated \u03b1-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice","volume-title":"Brain","author":"Shen","year":"2020"},{"key":"2024052508553119800_CIT0054","first-page":"719","article-title":"Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue","volume-title":"J Histochem Cytochem","author":"Schnell","year":"1999"},{"key":"2024052508553119800_CIT0055","first-page":"94","article-title":"Amyloid structure determination in RELION-3.1","volume-title":"Acta crystallogr D Struct Biol","author":"Scheres","year":"2020"},{"key":"2024052508553119800_CIT0056","first-page":"486","article-title":"Features and development of Coot","volume-title":"Acta Crystallogr Sect D Biol Crystallogr","author":"Emsley","year":"2010"},{"key":"2024052508553119800_CIT0057","first-page":"213","article-title":"PHENIX: a comprehensive Python-based system for macromolecular structure solution","volume-title":"Acta Crystallogr Sect D Biol Crystallogr","author":"Adams","year":"2010"}],"container-title":["Life 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