{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:17:43Z","timestamp":1792642663795,"version":"4.5.0"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"crossref","award":["MC_U105184291"],"award-info":[{"award-number":["MC_U105184291"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T \u03b1-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T \u03b1-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II \u03b1-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 \u03b1-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 \u03b1-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T \u03b1-synuclein or cerebellar extract with type II \u03b1-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of \u03b1-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of \u03b1-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein.<\/jats:p>","DOI":"10.1186\/s40478-021-01291-7","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T12:03:17Z","timestamp":1637755397000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Assembly of \u03b1-synuclein and neurodegeneration in the central nervous system of heterozygous\u00a0M83 mice following the peripheral administration of \u03b1-synuclein seeds"],"prefix":"10.1186","volume":"9","author":[{"given":"Jennifer A.","family":"Macdonald","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Masuda-Suzukake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Schweighauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zane","family":"Jaunmuktane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Warner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice L.","family":"Holton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle","family":"Grossman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Berks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Lavenir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Goedert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"key":"1291_CR1","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41582-020-0333-7","volume":"16","author":"C Peng","year":"2020","unstructured":"Peng C, Trojanowski JQ, Lee VMY (2020) Protein transmission in neurodegenerative disease. Nature Rev Neurol 16:199\u2013212","journal-title":"Nature Rev Neurol"},{"key":"1291_CR2","first-page":"S53","volume":"7","author":"M Goedert","year":"2017","unstructured":"Goedert M, Jakes R, Spillantini MG (2017) The Synucleinopathies: twenty years on. J Parkinsons Dis 7:S53\u2013S71","journal-title":"J Parkinsons Dis"},{"key":"1291_CR3","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","volume":"276","author":"MH Polymeropoulos","year":"1997","unstructured":"Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson\u2019s disease. Science 276:2045\u20132047","journal-title":"Science"},{"key":"1291_CR4","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1126\/science.1090278","volume":"302","author":"AB Singleton","year":"2003","unstructured":"Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J et al (2003) alpha-Synuclein locus triplication causes Parkinson\u2019s disease. Science 302:841","journal-title":"Science"},{"key":"1291_CR5","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1038\/ng.3043","volume":"46","author":"MA Nalls","year":"2014","unstructured":"Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M et al (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson\u2019s disease. Nature Genet 46:989\u2013993","journal-title":"Nature Genet"},{"key":"1291_CR6","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak H, Del Tredici K, R\u00fcb U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson\u2019s disease. Neurobiol Aging 24:197\u2013211","journal-title":"Neurobiol Aging"},{"key":"1291_CR7","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/nm1747","volume":"14","author":"JH Kordower","year":"2008","unstructured":"Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic neural transplants in Parkinson\u2019s disease. Nature Med 14:504\u2013506","journal-title":"Nature Med"},{"key":"1291_CR8","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/nm1746","volume":"14","author":"JY Li","year":"2008","unstructured":"Li JY, Englund E, Holton JL, Sopulet D, Hageli P, Lees AJ et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson\u2019s disease suggest host-to-graft disease propagation. Nature Med 14:501\u2013503","journal-title":"Nature Med"},{"key":"1291_CR9","doi-asserted-by":"publisher","first-page":"2225","DOI":"10.1016\/j.neurobiolaging.2011.06.022","volume":"33","author":"AL Mougenot","year":"2012","unstructured":"Mougenot AL, Nicot S, Bencsik A, Morignat E, Verch\u00e8re J, Lakhdar L et al (2012) Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 33:2225\u20132228","journal-title":"Neurobiol Aging"},{"key":"1291_CR10","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1126\/science.1227157","volume":"338","author":"KC Luk","year":"2012","unstructured":"Luk KC, Kehm V, Carroll J, Zhang B, O\u2019Brien P, Trojanowski JQ et al (2012) Pathological \u03b1-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949\u2013953","journal-title":"Science"},{"key":"1291_CR11","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1093\/brain\/awt037","volume":"136","author":"M Masuda-Suzukake","year":"2013","unstructured":"Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H et al (2013) Prion-like spreading of pathological \u03b1-synuclein in brain. Brain 136:1128\u20131138","journal-title":"Brain"},{"key":"1291_CR12","doi-asserted-by":"publisher","first-page":"19555","DOI":"10.1073\/pnas.1318268110","volume":"110","author":"JC Watts","year":"2013","unstructured":"Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM et al (2013) Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA 110:19555\u201319560","journal-title":"Proc Natl Acad Sci USA"},{"key":"1291_CR13","doi-asserted-by":"publisher","first-page":"10732","DOI":"10.1073\/pnas.1321785111","volume":"111","author":"AN Sacino","year":"2014","unstructured":"Sacino AN, Brooks M, Thomas MA, McKinney AB, Lee S, Regenhardt RW et al (2014) Intramuscular injection of \u03b1-synuclein induces CNS \u03b1-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci USA 111:10732\u201310737","journal-title":"Proc Natl Acad Sci USA"},{"key":"1291_CR14","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, Gugliano M et al (2015) \u03b1-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340\u2013344","journal-title":"Nature"},{"key":"1291_CR15","doi-asserted-by":"publisher","first-page":"9182","DOI":"10.1128\/JVI.01399-16","volume":"90","author":"S Breid","year":"2016","unstructured":"Breid S, Bernis ME, Babila JT, Garza MC, Wille H, Tamg\u00fcney G (2016) Neuroinvasion of \u03b1-synuclein prionoids after intraperitoneal and intraglossal inoculation. J Virol 90:9182\u20139193","journal-title":"J Virol"},{"key":"1291_CR16","doi-asserted-by":"publisher","first-page":"e02095","DOI":"10.1128\/JVI.02095-16","volume":"91","author":"JI Ayers","year":"2017","unstructured":"Ayers JI, Brooks MM, Rutherford NJ, Howard JK, Sorrentino ZA, Riffe CJ et al (2017) Robust central nervous system pathology in transgenic mice following peripheral injection of \u03b1-synuclein fibrils. J Virol 91:e02095-e2116","journal-title":"J Virol"},{"key":"1291_CR17","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s00401-017-1762-2","volume":"135","author":"AL Woerman","year":"2018","unstructured":"Woerman AL, Kazmi SA, Patel S, Freyman Y, Oehler A, Aoyagi A et al (2018) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135:49\u201363","journal-title":"Acta Neuropathol"},{"key":"1291_CR18","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1038\/s41467-019-14189-9","volume":"11","author":"XJ Wang","year":"2020","unstructured":"Wang XJ, Ma MM, Zhou LB, Jiang XY, Hao MM, Teng RKF et al (2020) Autonomic ganglionic injection of \u03b1-synuclein fibrils as a model of pure autonomic failure \u03b1-synucleinopathy. Nature Commun 11:934","journal-title":"Nature Commun"},{"key":"1291_CR19","doi-asserted-by":"publisher","first-page":"101166","DOI":"10.1016\/j.isci.2020.101166","volume":"23","author":"X Ding","year":"2020","unstructured":"Ding X, Zhou L, Jiang X, Liu H, Yao J, Zhang R et al (2020) Propagation of pathological \u03b1-synuclein from the urogenital tract to the brain initiates MSA-like syndrome. iScience 23:101166","journal-title":"iScience"},{"key":"1291_CR20","doi-asserted-by":"publisher","first-page":"6649","DOI":"10.1523\/JNEUROSCI.0189-20.2020","volume":"40","author":"WT Chu","year":"2020","unstructured":"Chu WT, DeSimone JC, Riffe CJ, Liu H, Chakrabarty P, Giasson BI et al (2020) \u03b1-Synuclein induces progressive changes in brain microstructure and sensory-evoked brain function that precedes locomotor decline. J Neurosci 40:6649\u20136659","journal-title":"J Neurosci"},{"key":"1291_CR21","doi-asserted-by":"publisher","first-page":"e00586","DOI":"10.1128\/JVI.00586-18","volume":"92","author":"JI Ayers","year":"2018","unstructured":"Ayers JI, Riffe CJ, Sorrentino ZA, Diamond J, Fagerli E, Brooks M et al (2018) Localized induction of wild-type and mutant alpha-synuclein aggregation reveals propagation along neuroanatomical tracts. J Virol 92:e00586-e618","journal-title":"J Virol"},{"key":"1291_CR22","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.nbd.2018.09.005","volume":"120","author":"ZA Sorrentino","year":"2018","unstructured":"Sorrentino ZA, Xia Y, Funk C, Riffe CJ, Rutherford NJ, Ceballos Diaz C et al (2018) Motor neuron loss and neuroinflammation in a model of \u03b1-synuclein-induced neurodegeneration. Neurobiol Dis 120:98\u2013106","journal-title":"Neurobiol Dis"},{"key":"1291_CR23","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s40478-021-01131-8","volume":"9","author":"N Ferreira","year":"2021","unstructured":"Ferreira N, Gon\u00e7alves NP, Jan A, Jensen NM, van der Laan A, Mohseni S et al (2021) Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain. Acta Neuropathol Commun 9:31","journal-title":"Acta Neuropathol Commun"},{"key":"1291_CR24","doi-asserted-by":"publisher","first-page":"fcab104","DOI":"10.1093\/braincomms\/fcab104","volume":"3","author":"N Ferreira","year":"2021","unstructured":"Ferreira N, Richner M, van der Laan A, Christiansen IBJ, V\u00e6gter CB, Nyengaard JR et al (2021) Prodromal neuroinvasion of pathological \u03b1-synuclein in brainstem reticular nuclei and white matter lesions in a model of \u03b1-synucleinopathy. Brain Commun 3:fcab104","journal-title":"Brain Commun"},{"key":"1291_CR25","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1007\/s00401-019-02037-5","volume":"138","author":"S Lohmann","year":"2019","unstructured":"Lohmann S, Bernis ME, Tachu BJ, Ziemski A, Grigoletto J, Tamg\u00fcney G (2019) Oral and intravenous transmission of \u03b1-synuclein fibrils to mice. Acta Neuropathol 138:515\u2013533","journal-title":"Acta Neuropathol"},{"key":"1291_CR26","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1111\/j.1365-2990.2007.00874.x","volume":"33","author":"CH Hawkes","year":"2007","unstructured":"Hawkes CH, Del Tredici K, Braak H (2007) Parkinson\u2019s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599\u2013614","journal-title":"Neuropathol Appl Neurobiol"},{"key":"1291_CR27","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/S1474-4422(06)70373-8","volume":"5","author":"KR Chaudhuri","year":"2006","unstructured":"Chaudhuri KR, Healy DG, Schapira AHV (2006) Non-motor symptoms of Parkinson\u2019s disease: diagnosis and management. Lancet Neurol 5:235\u2013245","journal-title":"Lancet Neurol"},{"key":"1291_CR28","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1002\/ana.24448","volume":"78","author":"E Svensson","year":"2015","unstructured":"Svensson E, Horv\u00e1th-Puh\u00f3 E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P et al (2015) Vagotomy and subsequent risk of Parkinson\u2019s disease. Ann Neurol 78:522\u2013529","journal-title":"Ann Neurol"},{"key":"1291_CR29","doi-asserted-by":"publisher","first-page":"1996","DOI":"10.1212\/WNL.0000000000003961","volume":"23","author":"B Liu","year":"2017","unstructured":"Liu B, Fang F, Pedersen NL, Tillander A, Ludvigsson JF, Ekbom A et al (2017) Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology 23:1996\u20132002","journal-title":"Neurology"},{"key":"1291_CR30","doi-asserted-by":"publisher","first-page":"9320","DOI":"10.1128\/JVI.75.19.9320-9327.2001","volume":"75","author":"PA McBride","year":"2001","unstructured":"McBride PA, Schulz-Schaeffer WJ, Donaldson M, Bruce M, Diringer H, Kretzschmar HA et al (2001) Early spread of scrapie from the gastrointestinal tract to the central nervous system involves autonomic fibers of the splanchnic and vagus nerves. J Virol 75:9320\u20139327","journal-title":"J Virol"},{"key":"1291_CR31","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1099\/0022-1317-79-3-601","volume":"79","author":"M Beekes","year":"1998","unstructured":"Beekes M, McBride PA, Baldauf E (1998) Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J Gen Virol 79:601\u2013607","journal-title":"J Gen Virol"},{"key":"1291_CR32","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/S0896-6273(02)00682-7","volume":"34","author":"BI Giasson","year":"2002","unstructured":"Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VMY (2002) Neuronal \u03b1-synucleinopathy with severe movement disorder in mice expressing A53T human \u03b1-synuclein. Neuron 34:521\u2013533","journal-title":"Neuron"},{"key":"1291_CR33","doi-asserted-by":"publisher","first-page":"2380","DOI":"10.1074\/jbc.M008919200","volume":"276","author":"BI Giasson","year":"2001","unstructured":"Giasson BI, Murray IVJ, Trojanowski JQ, Lee VMY (2001) A hydrophobic stretch of 12 amino acid residues in the middle of \u03b1-synuclein is essential for filament assembly. J Biol Chem 276:2380\u20132386","journal-title":"J Biol Chem"},{"key":"1291_CR34","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/j.jmb.2007.09.039","volume":"374","author":"S Zibaee","year":"2007","unstructured":"Zibaee S, Jakes R, Fraser G, Serpell LC, Crowther RA, Goedert M (2007) Sequence determinants for amyloid fibrillogenesis of human \u03b1-synuclein. J Mol Biol 374:454\u2013464","journal-title":"J Mol Biol"},{"key":"1291_CR35","doi-asserted-by":"publisher","first-page":"6652","DOI":"10.1074\/jbc.RA119.012179","volume":"295","author":"SA Morgan","year":"2020","unstructured":"Morgan SA, Lavenir I, Fan J, Masuda-Suzukake M, Passarella D, DeTure MA et al (2020) \u03b1-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species. J Biol Chem 295:6652\u20136664","journal-title":"J Biol Chem"},{"key":"1291_CR36","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/0896-6273(92)90117-V","volume":"8","author":"M Goedert","year":"1992","unstructured":"Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159\u2013168","journal-title":"Neuron"},{"key":"1291_CR37","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1007\/s00401-018-1914-z","volume":"136","author":"B Falcon","year":"2018","unstructured":"Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ et al (2018) Tau filaments from multiple cases of sporadic and inherited Alzheimer\u2019s disease adopt a common fold. Acta Neuropathol 136:699\u2013708","journal-title":"Acta Neuropathol"},{"key":"1291_CR38","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 (2020) Structures of \u03b1-synuclein filaments from multiple system atrophy. Nature 585:464\u2013469","journal-title":"Nature"},{"key":"1291_CR39","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1007\/s00401-021-02294-3","volume":"141","author":"Y Shi","year":"2021","unstructured":"Shi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P et al (2021) Cryo-EM structures of tau filaments from Alzheimer\u2019s disease with PET ligand APN-1607. Acta Neuropathol 141:697\u2013708","journal-title":"Acta Neuropathol"},{"key":"1291_CR40","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s40478-019-0695-5","volume":"7","author":"JA Macdonald","year":"2019","unstructured":"Macdonald JA, Bronner IF, Drynan L, Fan J, Curry A, Fraser G et al (2019) Assembly of transgenic human P301S tau is necessary for neurodegeneration in murine spinal cord. Acta Neuropathol Commun 7:44","journal-title":"Acta Neuropathol Commun"},{"key":"1291_CR41","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/ncb748","volume":"4","author":"H Fujiwara","year":"2000","unstructured":"Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS et al (2000) Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160\u2013164","journal-title":"Nat Cell Biol"},{"key":"1291_CR42","doi-asserted-by":"publisher","first-page":"29739","DOI":"10.1074\/jbc.M600933200","volume":"281","author":"JP Anderson","year":"2006","unstructured":"Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of \u03b1-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739\u201329752","journal-title":"J Biol Chem"},{"key":"1291_CR43","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/S0304-3940(98)00504-7","volume":"251","author":"MG Spillantini","year":"1998","unstructured":"Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous \u03b1-synuclein inclusions link multiple system atrophy with Parkinson\u2019s disease and dementia with Lewy bodies. Neurosci Lett 251:205\u2013208","journal-title":"Neurosci Lett"},{"key":"1291_CR44","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1007\/s00401-014-1343-6","volume":"128","author":"S Holmqvist","year":"2014","unstructured":"Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bj\u00f6rklund T et al (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128:805\u2013820","journal-title":"Acta Neuropathol"},{"key":"1291_CR45","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s40478-014-0142-6","volume":"2","author":"WJ Streit","year":"2014","unstructured":"Streit WJ, Xue QS, Tischer T, Bechmann I (2014) Microglial pathology. Acta Neuropathol Commun 2:142","journal-title":"Acta Neuropathol Commun"},{"key":"1291_CR46","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1007\/s00401-019-02040-w","volume":"138","author":"N Van Den Berge","year":"2019","unstructured":"Van Den Berge N, Ferreira N, Gram H, Werenberg Mikkelsen T, Alstrup AKO, Casadei N et al (2019) Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats. Acta Neuropathol 138:535\u2013550","journal-title":"Acta Neuropathol"},{"key":"1291_CR47","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1111\/bpa.12168","volume":"25","author":"K Seidel","year":"2015","unstructured":"Seidel K, Mahlke J, Siswanto S, Kr\u00fcger R, Heinsen H, Auburger G et al (2015) The brainstem pathologies of Parkinson\u2019s disease and dementia with Lewy bodies. Brain Pathol 25:121\u2013135","journal-title":"Brain Pathol"},{"key":"1291_CR48","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 (2020) \u03b1-Synuclein strains target distinct brain regions and cell types. Nature Neurosci 23:21\u201331","journal-title":"Nature Neurosci"},{"key":"1291_CR49","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/nature15369","volume":"525","author":"Z Jaunmuktane","year":"2015","unstructured":"Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J et al (2015) Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature 525:247\u2013250","journal-title":"Nature"},{"key":"1291_CR50","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.neuron.2019.05.035","volume":"103","author":"S Kim","year":"2019","unstructured":"Kim S, Kwon SH, Kam T, Panicker N, Karuppagounder SS, Lee S et al (2019) Transneuronal propagation of pathologic \u03b1-synuclein from the gut to the brain models Parkinson\u2019s disease. Neuron 103:627\u2013641","journal-title":"Neuron"},{"key":"1291_CR51","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/s41380-021-01033-0","volume":"26","author":"WL Kuan","year":"2019","unstructured":"Kuan WL, Stott K, He X, Wood TC, Yang S, Kwok JCF et al (2019) Systemic \u03b1-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson\u2019s disease. Mol Psychiatry 26:365","journal-title":"Mol Psychiatry"},{"key":"1291_CR52","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1084\/jem.20160368","volume":"213","author":"NL Rey","year":"2016","unstructured":"Rey NL, Steiner JA, Maroof N, Luk KC, Madaj Z, Trojanowski JQ et al (2016) Widespread transneuronal propagation of \u03b1-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson\u2019s disease. J Exp Med 213:1759\u20131778","journal-title":"J Exp Med"},{"key":"1291_CR53","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1016\/j.celrep.2015.01.060","volume":"10","author":"VR Osterberg","year":"2015","unstructured":"Osterberg VR, Spinelli KJ, Weston LJ, Luk KC, Woltjer RL, Unni VK (2015) Progressive aggregation of alpha-synuclein and selective neurodegeneration of Lewy inclusion-bearing neurons in a mouse model of parkinsonism. Cell Rep 10:1252\u20131260","journal-title":"Cell Rep"},{"key":"1291_CR54","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1038\/nsmb.3194","volume":"23","author":"MD Tuttle","year":"2016","unstructured":"Tuttle MD, Comellas G, Nieuwkoop AJ, Covell DJ, Berthold DA, Kloepper KD et al (2016) Solid-state NMR structure of a pathogenic fibril of full-length human \u03b1-synuclein. Nature Struct Mol Biol 23:409\u2013415","journal-title":"Nature Struct Mol Biol"},{"key":"1291_CR55","doi-asserted-by":"publisher","first-page":"e36402","DOI":"10.7554\/eLife.36402","volume":"7","author":"R Guerrero-Ferreira","year":"2018","unstructured":"Guerrero-Ferreira R, Taylor NMI, Mona D, Ringler P, Lauer ME, Riek R et al (2018) Cryo-EM structure of alpha-synuclein fibrils. Elife 7:e36402","journal-title":"Elife"},{"key":"1291_CR56","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1038\/s41422-018-0075-x","volume":"28","author":"Y Li","year":"2018","unstructured":"Li Y, Zhao C, Luo F, Liu Z, Gui X, Luo Z et al (2018) Amyloid fibril structure of \u03b1-synuclein determined by cryo-electron microscopy. Cell Res 28:897\u2013903","journal-title":"Cell Res"},{"key":"1291_CR57","doi-asserted-by":"publisher","first-page":"48907","DOI":"10.7554\/eLife.48907","volume":"8","author":"R Guerrero-Ferreira","year":"2019","unstructured":"Guerrero-Ferreira R, Taylor NMI, Arteni AA, Kumari P, Mona D, Ringler P et al (2019) Two new polymorphic structures of human full-length alpha-synuclein fibrils solved by cryo-electron microscopy. Elife 8:48907","journal-title":"Elife"},{"key":"1291_CR58","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1016\/j.cell.2012.02.022","volume":"148","author":"DS Eisenberg","year":"2012","unstructured":"Eisenberg DS, Jucker M (2012) The amyloid state of proteins in human diseases. Cell 148:1188\u20131203","journal-title":"Cell"},{"key":"1291_CR59","doi-asserted-by":"publisher","first-page":"E5308","DOI":"10.1073\/pnas.1514475112","volume":"112","author":"SB Prusiner","year":"2015","unstructured":"Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB et al (2015) Evidence for \u03b1-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci USA 112:E5308\u2013E5317","journal-title":"Proc Natl Acad Sci USA"},{"key":"1291_CR60","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 (2015) Propagation of prions causing synucleinopathies in cultured cells. Proc Natl Acad Sci USA 112:E4949\u2013E4958","journal-title":"Proc Natl Acad Sci USA"},{"key":"1291_CR61","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/s40478-019-0804-5","volume":"7","author":"I Lavenir","year":"2019","unstructured":"Lavenir I, Passarella D, Masuda-Suzukake M, Curry A, Holton JL et al (2019) Silver staining (Campbell-Switzer) of neuronal \u03b1-synuclein assemblies induced by multiple system atrophy and Parkinson\u2019s disease brain extracts in transgenic mice. Acta Neuropathol Commun 7:148","journal-title":"Acta Neuropathol Commun"},{"key":"1291_CR62","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, Stierber A, Robinson JL et al (2018) Cellular milieu imparts distinct pathological \u03b1-synuclein strains in \u03b1-synucleinopathies. Nature 557:558\u2013563","journal-title":"Nature"},{"key":"1291_CR63","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1186\/s40478-019-0840-1","volume":"7","author":"T Klingstedt","year":"2019","unstructured":"Klingstedt T, Ghetti B, Holton JL, Ling H, Nilsson KPR, Goedert M (2019) Luminescent conjugated oligothiophenes distinguish between alpha-synuclein assemblies of Parkinson\u2019s disease and multiple system atrophy. Acta Neuropathol Commun 7:193","journal-title":"Acta Neuropathol Commun"},{"key":"1291_CR64","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nri3705","volume":"14","author":"MT Heneka","year":"2004","unstructured":"Heneka MT, Kummer MP, Latz E (2004) Innate immune activation in neurodegenerative disease. Nature Rev Immunol 14:463\u2013477","journal-title":"Nature Rev Immunol"},{"key":"1291_CR65","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1186\/s40478-020-00993-8","volume":"8","author":"G Tanri\u00f6ver","year":"2020","unstructured":"Tanri\u00f6ver G, Bacioglu M, Schweighauser M, Mahler J, Wegenast-Braun BM, Skodras A et al (2020) Prominent microglial inclusions in transgenic mouse models of \u03b1-synucleinopathy that are distinct from neuronal lesions. Acta Neuropathol Commun 8:133","journal-title":"Acta Neuropathol Commun"},{"key":"1291_CR66","doi-asserted-by":"publisher","first-page":"5089","DOI":"10.1016\/j.cell.2021.09.007","volume":"184","author":"H Scheiblich","year":"2021","unstructured":"Scheiblich H, Dansokho C, Mercan D, Schmidt SV, Bousset L, Wischhof L et al (2021) Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell 184:5089-5106.e21","journal-title":"Cell"},{"key":"1291_CR67","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s40478-015-0209-z","volume":"3","author":"AD Bachstetter","year":"2015","unstructured":"Bachstetter AD, Van Eldik LJ, Schmitt FA, Neltner JH, Ighodaro ET, Webster SJ et al (2015) Disease-related microglia heterogeneity in the hippocampus of Alzheimer\u2019s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun 3:32","journal-title":"Acta Neuropathol Commun"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-021-01291-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-021-01291-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-021-01291-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T03:36:17Z","timestamp":1666841777000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-021-01291-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,24]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["1291"],"URL":"https:\/\/doi.org\/10.1186\/s40478-021-01291-7","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,24]]},"assertion":[{"value":"15 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2021","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This article has been updated to correct a minor error in the equal contribution statement.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Experiments were conducted in accordance with the UK Animals (Scientific Procedures) Act of 1986, with local ethical approval (MRC Laboratory of Molecular Biology Animal Welfare and Ethical Review Body Committee). The studies carried out at the UCL Queen Square Institute of Neurology and the Edinburgh Brain Bank were approved through the ethical review processes at each institution.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare that they have no competing interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interest"}}],"article-number":"189"}}