{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T02:53:12Z","timestamp":1794538392939,"version":"4.9.1"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T00:00:00Z","timestamp":1644192000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T00:00:00Z","timestamp":1644192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Rossy Foundation"},{"DOI":"10.13039\/501100004089","name":"Krembil Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003136","name":"Edmond J. Safra Philanthropic Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003136","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Neurodegener"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of \u03b1-synuclein both between different patients and between different brain regions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The reliable detection of \u03b1-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of \u03b1-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived \u03b1-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in \u03b1-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of \u03b1-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We have identified unexpected differences in seed-competent \u03b1-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble \u03b1-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of \u03b1-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40035-022-00283-4","type":"journal-article","created":{"date-parts":[[2022,2,6]],"date-time":"2022-02-06T22:02:26Z","timestamp":1644184946000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":101,"title":["Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy"],"prefix":"10.1186","volume":"11","author":[{"given":"Ivan","family":"Martinez-Valbuena","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi P.","family":"Visanji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ain","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather H. C.","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphaella W. L.","family":"So","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohaila","family":"Alshimemeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Seidman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R.","family":"Luquin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel C.","family":"Watts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony E.","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3841-5511","authenticated-orcid":false,"given":"Gabor G.","family":"Kovacs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,2,7]]},"reference":[{"key":"283_CR1","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1212\/01.wnl.0000324625.00404.15","volume":"71","author":"S Gilman","year":"2008","unstructured":"Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71:670\u20136.","journal-title":"Neurology"},{"key":"283_CR2","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1136\/jnnp.32.1.28","volume":"32","author":"JG Graham","year":"1969","unstructured":"Graham JG, Oppenheimer DR. Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiatry. 1969;32:28\u201334.","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"283_CR3","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/0022-510X(89)90219-0","volume":"94","author":"MI Papp","year":"1989","unstructured":"Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci. 1989;94:79\u2013100.","journal-title":"J Neurol Sci"},{"key":"283_CR4","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/S0304-3940(98)00504-7","volume":"251","author":"M Grazia Spillantini","year":"1998","unstructured":"Grazia Spillantini M, Anthony Crowther R, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous \u03b1-synuclein inclusions link multiple system atrophy with Parkinson\u2019s disease and dementia with Lewy bodies. Neurosci Lett. 1998;251:205\u20138.","journal-title":"Neurosci Lett"},{"key":"283_CR5","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/nature14547","volume":"522","author":"W Peelaerts","year":"2015","unstructured":"Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, et al. \u03b1-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature. 2015;522:340\u20134.","journal-title":"Nature"},{"key":"283_CR6","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s00401-020-02163-5","volume":"142","author":"SAM Holec","year":"2020","unstructured":"Holec SAM, Woerman AL. Evidence of distinct \u03b1\u2014synuclein strains underlying disease heterogeneity. Acta Neuropathol. 2020;142:73\u201386.","journal-title":"Acta Neuropathol"},{"key":"283_CR7","doi-asserted-by":"publisher","first-page":"E4949","DOI":"10.1073\/pnas.1513426112","volume":"112","author":"AL Woerman","year":"2015","unstructured":"Woerman AL, St\u00f6hr J, Aoyagi A, Rampersaud R, Krejciova Z, Watts JC, et al. Propagation of prions causing synucleinopathies in cultured cells. Proc Natl Acad Sci U S A. 2015;112:E4949\u201358.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"283_CR8","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1038\/s41586-018-0104-4","volume":"557","author":"C Peng","year":"2018","unstructured":"Peng C, Gathagan RJ, Covell DJ, Medellin C, Stieber A, Robinson JL, et al. Cellular milieu imparts distinct pathological \u03b1-synuclein strains in \u03b1-synucleinopathies. Nature. 2018;557:558\u201363.","journal-title":"Nature"},{"key":"283_CR9","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/s41586-020-2317-6","volume":"585","author":"M Schweighauser","year":"2020","unstructured":"Schweighauser M, Shi Y, Tarutani A, Kametani F, Murzin AG, Ghetti B, et al. Structures of \u03b1-synuclein filaments from multiple system atrophy. Nature. 2020;585:464\u20139.","journal-title":"Nature"},{"key":"283_CR10","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.conb.2020.01.014","volume":"61","author":"R Guerrero-Ferreira","year":"2020","unstructured":"Guerrero-Ferreira R, Kovacik L, Ni D, Stahlberg H. New insights on the structure of alpha-synuclein fibrils using cryo-electron microscopy. Curr Opin Neurobiol. 2020;61:89\u201395.","journal-title":"Curr Opin Neurobiol"},{"key":"283_CR11","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.cll.2020.04.002","volume":"40","author":"N do Carmo-Ferreira","year":"2020","unstructured":"do Carmo-Ferreira N, Caughey B. Proteopathic seed amplification assays for neurodegenerative disorders. Clin Lab Med. 2020;40:257\u201370.","journal-title":"Clin Lab Med"},{"key":"283_CR12","doi-asserted-by":"publisher","first-page":"2233","DOI":"10.1038\/nprot.2016.120","volume":"11","author":"M Schmitz","year":"2016","unstructured":"Schmitz M, Cramm M, Llorens F, M\u00fcller-Cramm D, Collins S, Atarashi R, et al. The real-time quaking-induced conversion assay for detection of human prion disease and study of other protein misfolding diseases. Nat Protoc. 2016;11:2233\u201342.","journal-title":"Nat Protoc"},{"key":"283_CR13","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1001\/jamaneurol.2016.4614","volume":"74","author":"M Bongianni","year":"2017","unstructured":"Bongianni M, Orr\u00f9 C, Groveman BR, Sacchetto L, Fiorini M, Tonoli G, et al. Diagnosis of human prion disease using real-time quaking-induced conversion testing of olfactory mucosa and cerebrospinal fluid samples. JAMA Neurol. 2017;74:155\u201362.","journal-title":"JAMA Neurol"},{"key":"283_CR14","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1002\/mds.27907","volume":"35","author":"S Manne","year":"2020","unstructured":"Manne S, Kondru N, Jin H, Anantharam V, Huang X, Kanthasamy A, et al. \u03b1-Synuclein real-time quaking-induced conversion in the submandibular glands of Parkinson\u2019s disease patients. Mov Disord. 2020;35:268\u201378.","journal-title":"Mov Disord"},{"key":"283_CR15","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1001\/jamaneurol.2020.3311","volume":"78","author":"Z Wang","year":"2021","unstructured":"Wang Z, Becker K, Donadio V, Siedlak S, Yuan J, Rezaee M, et al. Skin \u03b1-synuclein aggregation seeding activity as a novel biomarker for Parkinson disease. JAMA Neurol. 2021;78:30.","journal-title":"JAMA Neurol"},{"issue":"5","key":"283_CR16","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1002\/ana.25447","volume":"85","author":"A van Rumund","year":"2019","unstructured":"van Rumund A, Green AJ, Fairfoul G, Esselink RA, Bloem BR, Verbeek MM. Alpha-synuclein RT-QuIC in the CSF of uncertain cases of parkinsonism. Ann Neurol. 2019;85(5):777\u201381.","journal-title":"Ann Neurol"},{"key":"283_CR17","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s00401-020-02160-8","volume":"140","author":"M Rossi","year":"2020","unstructured":"Rossi M, Candelise N, Baiardi S, Capellari S, Giannini G, Orr\u00f9 CD, et al. Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol. 2020;140:49\u201362.","journal-title":"Acta Neuropathol"},{"key":"283_CR18","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/s41586-020-1984-7","volume":"578","author":"M Shahnawaz","year":"2020","unstructured":"Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, Liu X, et al. Discriminating \u03b1-synuclein strains in Parkinson\u2019s disease and multiple system atrophy. Nature. 2020;578:273\u20137.","journal-title":"Nature"},{"key":"283_CR19","doi-asserted-by":"publisher","first-page":"23029","DOI":"10.1073\/pnas.1909322116","volume":"116","author":"MA Metrick","year":"2019","unstructured":"Metrick MA, do Carmo Ferreira N, Saijo E, Hughson AG, Kraus A, Orr\u00fa C, et al. Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons. Proc Natl Acad Sci U S A. 2019;116:23029\u201339.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"283_CR20","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1136\/jclinpath-2019-205952","volume":"72","author":"GG Kovacs","year":"2019","unstructured":"Kovacs GG. Molecular pathology of neurodegenerative diseases: principles and practice. J Clin Pathol. 2019;72:725\u201335.","journal-title":"J Clin Pathol"},{"issue":"8","key":"283_CR21","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1038\/s41591-020-0938-9","volume":"26","author":"S Dujardin","year":"2020","unstructured":"Dujardin S, Commins C, Lathuiliere A, Beerepoot P, Fernandes AR, Kamath TV, et al. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer\u2019s disease. Nat Med. 2020;26(8):1256\u201363.","journal-title":"Nat Med"},{"key":"283_CR22","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1111\/neup.12708","volume":"41","author":"S Klotz","year":"2021","unstructured":"Klotz S, Fischer P, Hinterberger M, Ricken G, H\u00f6nigschnabl S, Gelpi E, et al. Multiple system aging-related tau astrogliopathy with complex proteinopathy in an oligosymptomatic octogenarian. Neuropathology. 2021;41:72\u201383.","journal-title":"Neuropathology"},{"key":"283_CR23","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s00401-012-0964-x","volume":"124","author":"GG Kovacs","year":"2012","unstructured":"Kovacs GG, Wagner U, Dumont B, Pikkarainen M, Osman AA, Streichenberger N, et al. An antibody with high reactivity for disease-associated \u03b1-synuclein reveals extensive brain pathology. Acta Neuropathol. 2012;124:37\u201350.","journal-title":"Acta Neuropathol"},{"key":"283_CR24","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41593-019-0541-x","volume":"23","author":"A Lau","year":"2020","unstructured":"Lau A, So RWL, Lau HHC, Sang JC, Ruiz-Riquelme A, Fleck SC, et al. \u03b1-Synuclein strains target distinct brain regions and cell types. Nat Neurosci. 2020;23:21\u201331.","journal-title":"Nat Neurosci"},{"key":"283_CR25","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.1093\/brain\/awh303","volume":"127","author":"T Ozawa","year":"2004","unstructured":"Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, Kilford L, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain. 2004;127:2657\u201371.","journal-title":"Brain"},{"key":"283_CR26","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1007\/s004010050655","volume":"93","author":"M Inoue","year":"1997","unstructured":"Inoue M, Yagishita S, Ryo M, Hasegawa K, Amano N, Matsushita M. The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems. Acta Neuropathol. 1997;93:585\u201391.","journal-title":"Acta Neuropathol"},{"key":"283_CR27","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1002\/ana.25446","volume":"85","author":"N Candelise","year":"2019","unstructured":"Candelise N, Schmitz M, Llorens F, Villar-Piqu\u00e9 A, Cramm M, Thom T, et al. Seeding variability of different alpha synuclein strains in synucleinopathies. Ann Neurol. 2019;85:691\u2013703.","journal-title":"Ann Neurol"},{"key":"283_CR28","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1002\/ana.25447","volume":"85","author":"A van Rumund","year":"2019","unstructured":"van Rumund A, Green AJE, Fairfoul G, Esselink RAJ, Bloem BR, Verbeek MM. \u03b1-Synuclein real-time quaking-induced conversion in the cerebrospinal fluid of uncertain cases of parkinsonism. Ann Neurol. 2019;85:777\u201381.","journal-title":"Ann Neurol"},{"key":"283_CR29","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/s004019900177","volume":"100","author":"K Ishizawa","year":"2000","unstructured":"Ishizawa K, Ksiezak-Reding H, Davies P, Delacourte A, Tiseo P, Yen SH, et al. A double-labeling immunohistochemical study of tau exon 10 in Alzheimer\u2019s disease, progressive supranuclear palsy and Pick\u2019s disease. Acta Neuropathol. 2000;100:235\u201344.","journal-title":"Acta Neuropathol"},{"key":"283_CR30","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1002\/ana.25824","volume":"88","author":"W Singer","year":"2020","unstructured":"Singer W, Schmeichel AM, Shahnawaz M, Schmelzer JD, Boeve BF, Sletten DM, et al. Alpha-synuclein oligomers and neurofilament light chain in spinal fluid differentiate multiple system atrophy from lewy body synucleinopathies. Ann Neurol. 2020;88:503\u201312.","journal-title":"Ann Neurol"},{"key":"283_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40035-019-0181-9","volume":"9","author":"N Candelise","year":"2020","unstructured":"Candelise N, Schmitz M, Th\u00fcne K, Cramm M, Rabano A, Zafar S, et al. Effect of the micro-environment on \u03b1-synuclein conversion and implication in seeded conversion assays. Transl Neurodegen. 2020;9:1\u201316.","journal-title":"Transl Neurodegen"},{"key":"283_CR32","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1007\/s00401-019-01961-w","volume":"137","author":"H Sekiya","year":"2019","unstructured":"Sekiya H, Kowa H, Koga H, Takata M, Satake W, Futamura N, et al. Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation. Acta Neuropathol. 2019;137:455\u201366.","journal-title":"Acta Neuropathol"},{"key":"283_CR33","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1016\/S0002-9440(10)65226-1","volume":"155","author":"DW Dickson","year":"1999","unstructured":"Dickson DW, Liu WK, Hardy J, Farrer M, Mehta N, Uitti R, et al. Widespread alterations of \u03b1-synuclein in multiple system atrophy. Am J Pathol. 1999;155:1241\u201351.","journal-title":"Am J Pathol"},{"key":"283_CR34","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1046\/j.1471-4159.2001.00021.x","volume":"76","author":"BCV Campbell","year":"2001","unstructured":"Campbell BCV, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, J\u00e4k\u00e4l\u00e4 P, et al. The solubility of \u03b1-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson\u2019s disease. J Neurochem. 2001;76:87\u201396.","journal-title":"J Neurochem"},{"key":"283_CR35","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.3390\/biom10091233","volume":"10","author":"M Manca","year":"2020","unstructured":"Manca M, Kraus A. Defining the protein seeds of neurodegeneration using real-time quaking-induced conversion assays. Biomolecules. 2020;10:1233.","journal-title":"Biomolecules"},{"issue":"1","key":"283_CR36","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/s00401-021-02316-0","volume":"142","author":"N Ferreira","year":"2021","unstructured":"Ferreira N, Gram H, Sorrentino ZA, Gregersen E, Ida S, Lasse S, et al. Multiple system atrophy - associated oligodendroglial protein p25\u03b1 stimulates formation of novel \u03b1\u2014synuclein strain with enhanced neurodegenerative potential. Acta Neuropathol. 2021;142(1):87\u2013115.","journal-title":"Acta Neuropathol"}],"container-title":["Translational Neurodegeneration"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40035-022-00283-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40035-022-00283-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40035-022-00283-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T10:03:55Z","timestamp":1644228235000},"score":1,"resource":{"primary":{"URL":"https:\/\/translationalneurodegeneration.biomedcentral.com\/articles\/10.1186\/s40035-022-00283-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,7]]},"references-count":36,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["283"],"URL":"https:\/\/doi.org\/10.1186\/s40035-022-00283-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.08.10.455800","asserted-by":"object"}]},"ISSN":["2047-9158"],"issn-type":[{"value":"2047-9158","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,7]]},"assertion":[{"value":"29 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 February 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the University Health Network Research Ethics Board (Nr. 20-5258). Furthermore, autopsy tissues from human brains were collected with informed consent of patients or their relatives and approval from local institutional review boards.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"GGK holds shared patent for the 5G4 antibody. Other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7"}}