{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:46:17Z","timestamp":1790178377129,"version":"4.1.0"},"reference-count":165,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,12,19]],"date-time":"2018-12-19T00:00:00Z","timestamp":1545177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001791","name":"Griffith University","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/501100001791","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001230","name":"Macquarie University","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/501100001230","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple system atrophy, characterized by atypical Parkinsonism, results from central nervous system (CNS) cell loss and dysfunction linked to aggregates of the normally pre-synaptic \u03b1-synuclein protein. Mostly cytoplasmic pathological \u03b1-synuclein inclusion bodies occur predominantly in oligodendrocytes in affected brain regions and there is evidence that \u03b1-synuclein released by neurons is taken up preferentially by oligodendrocytes. However, extracellular \u03b1-synuclein has also been shown to interact with other neural cell types, including astrocytes and microglia, as well as extracellular factors, mediating neuroinflammation, cell-to-cell spread and other aspects of pathogenesis. Here, we review the current evidence for how \u03b1-synuclein present in the extracellular milieu may act at the cell surface to drive components of disease progression. A more detailed understanding of the important extracellular interactions of \u03b1-synuclein with neuronal and non-neuronal cell types both in the brain and periphery may provide new therapeutic targets to modulate the disease process.<\/jats:p>","DOI":"10.3390\/ijms19124129","type":"journal-article","created":{"date-parts":[[2018,12,19]],"date-time":"2018-12-19T12:12:44Z","timestamp":1545221564000},"page":"4129","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Extracellular Interactions of Alpha-Synuclein in Multiple System Atrophy"],"prefix":"10.3390","volume":"19","author":[{"given":"Dario","family":"Valdinocci","sequence":"first","affiliation":[{"name":"School of Medical Science, Griffith University, Gold Coast 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowan A. W.","family":"Radford","sequence":"additional","affiliation":[{"name":"Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medical and Health Sciences, Macquarie University, Sydney 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Goulding","sequence":"additional","affiliation":[{"name":"School of Medical Science, Griffith University, Gold Coast 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junna","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Research School of Chemistry, Australian National University, Canberra 2601, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger S.","family":"Chung","sequence":"additional","affiliation":[{"name":"Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medical and Health Sciences, Macquarie University, Sydney 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean L.","family":"Pountney","sequence":"additional","affiliation":[{"name":"School of Medical Science, Griffith University, Gold Coast 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13709","DOI":"10.1021\/bi961799n","article-title":"NACP, A Protein Implicated in Alzheimer\u2019s Disease and Learning, Is Natively Unfolded","volume":"35","author":"Weinreb","year":"1996","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature16531","article-title":"Structural disorder of monomeric \u03b1-synuclein persists in mammalian cells","volume":"530","author":"Theillet","year":"2016","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000112832","article-title":"Red Blood Cells Are the Major Source of A-Synuclein in Blood","volume":"5","author":"Barbour","year":"2008","journal-title":"Neurodegener. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3233\/JAD-2002-4406","article-title":"Platelet alpha- and gamma-synucleins in Parkinson\u2019s disease and normal control subjects","volume":"4","author":"Li","year":"2002","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s10059-000-0065-x","article-title":"Expression patterns of alpha-synuclein in human hematopoietic cells and in Drosophila at different developmental stages","volume":"10","author":"Shin","year":"2000","journal-title":"Mol. Cells"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jchemneu.2010.12.001","article-title":"The role of \u03b1-synuclein in neurotransmission and synaptic plasticity","volume":"42","author":"Cheng","year":"2011","journal-title":"J. Chem. Neuroanat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"699","DOI":"10.3233\/JPD-150642","article-title":"The Synaptic Function of \u03b1-Synuclein","volume":"5","year":"2015","journal-title":"J. Parkinsons. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1126\/science.1195227","article-title":"\u03b1-Synuclein Promotes SNARE-Complex Assembly in Vivo and in Vitro","volume":"329","author":"Burre","year":"2010","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3090","DOI":"10.1523\/JNEUROSCI.22-08-03090.2002","article-title":"A role for \u03b1-synuclein in the regulation of dopamine biosynthesis","volume":"22","author":"Perez","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11915","DOI":"10.1523\/JNEUROSCI.3821-06.2006","article-title":"\u03b1-Synuclein Overexpression in PC12 and Chromaffin Cells Impairs Catecholamine Release by Interfering with a Late Step in Exocytosis","volume":"26","author":"Larsen","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1111\/j.1471-4159.2006.04098.x","article-title":"Abnormal compartmentalization of norepinephrine in mouse dentate gyrus in \u03b1-synuclein knockout and A30P transgenic mice","volume":"99","author":"Yavich","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11165","DOI":"10.1523\/JNEUROSCI.2559-04.2004","article-title":"Role of \u03b1-Synuclein in Presynaptic Dopamine Recruitment","volume":"24","author":"Yavich","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13612","DOI":"10.1021\/bi050402p","article-title":"Disruption of the interaction of alpha-synuclein with microtubules enhances cell surface recruitment of the dopamine transporter","volume":"44","author":"Wersinger","year":"2005","journal-title":"Biochemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nature10324","article-title":"\u03b1-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation","volume":"477","author":"Bartels","year":"2011","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0014-5793(94)00395-5","article-title":"Identification of two distinct synucleins from human brain","volume":"345","author":"Jakes","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1021\/bi501188a","article-title":"Purification of \u03b1-Synuclein from Human Brain Reveals an Instability of Endogenous Multimers as the Protein Approaches Purity","volume":"54","author":"Luth","year":"2015","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7314","DOI":"10.1038\/ncomms8314","article-title":"Parkinson-causing \u03b1-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation","volume":"6","author":"Dettmer","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15345","DOI":"10.1074\/jbc.M111.318949","article-title":"\u03b1-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer","volume":"287","author":"Fauvet","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_19","first-page":"570","article-title":"Calcium: \u03b1-Synuclein Interactions in \u03b1-Synucleinopathies","volume":"10","author":"Osborne","year":"2016","journal-title":"Front. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/ncb748","article-title":"\u03b1-Synuclein is phosphorylated in synucleinopathy lesions","volume":"4","author":"Fujiwara","year":"2002","journal-title":"Nat. Cell. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1096\/fj.03-1449com","article-title":"Detection of oligomeric forms of \u03b1-synuclein protein in human plasma as a potential biomarker for Parkinson\u2019s disease","volume":"20","author":"Salem","year":"2006","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1111\/j.1471-4159.2007.05087.x","article-title":"Nitrated \u03b1-synuclein-activated microglial profiling for Parkinson\u2019s disease","volume":"104","author":"Reynolds","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3233\/JPD-160779","article-title":"Implication of Alpha-Synuclein Phosphorylation at S129 in Synucleinopathies: What Have We Learned in the Last Decade?","volume":"6","author":"Oueslati","year":"2016","journal-title":"J. Parkinsons. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.1016\/S1353-8020(13)70017-8","article-title":"\u03b1-Synucleinopathy phenotypes","volume":"20","author":"McCann","year":"2014","journal-title":"Park. Relat. Disord."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1002\/glia.22653","article-title":"\u03b1-Synuclein mRNA expression in oligodendrocytes in MSA","volume":"62","author":"Asi","year":"2014","journal-title":"Glia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.stemcr.2015.07.002","article-title":"\u03b1-Synuclein Expression in the Oligodendrocyte Lineage: An In Vitro and In Vivo Study Using Rodent and Human Models","volume":"5","author":"Djelloul","year":"2015","journal-title":"Stem Cell. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/glia.22611","article-title":"\u03b1-Synuclein transfers from neurons to oligodendrocytes","volume":"62","author":"Reyes","year":"2013","journal-title":"Glia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1056\/NEJMra1311488","article-title":"Multiple-System Atrophy","volume":"372","author":"Longo","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.tins.2011.08.003","article-title":"Multiple system atrophy: A clinical and neuropathological perspective","volume":"34","author":"Ubhi","year":"2011","journal-title":"Trends Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1096\/fj.10-164624","article-title":"Heat-shock protein 70 modulates toxic extracellular \u03b1-synuclein oligomers and rescues trans-synaptic toxicity","volume":"25","author":"Danzer","year":"2011","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.15252\/embj.201593489","article-title":"DnaJ\/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins","volume":"35","author":"Fontaine","year":"2016","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/1750-1326-7-42","article-title":"Exosomal cell-to-cell transmission of \u03b1 synuclein oligomers","volume":"7","author":"Danzer","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.nbd.2011.01.029","article-title":"Lysosomal dysfunction increases exosome-mediated \u03b1-synuclein release and transmission","volume":"42","author":"Seow","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6838","DOI":"10.1523\/JNEUROSCI.5699-09.2010","article-title":"Cell-Produced-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival","volume":"30","author":"Emmanouilidou","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nature14547","article-title":"\u03b1-Synuclein strains cause distinct synucleinopathies after local and systemic administration","volume":"522","author":"Peelaerts","year":"2015","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13024-018-0241-0","article-title":"Extracellular \u03b1-synuclein levels are regulated by neuronal activity","volume":"13","author":"Yamada","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_37","first-page":"1696","article-title":"Modulation of \u03b2-glucocerebrosidase increases \u03b1-synuclein secretion and exosome release in mouse models of Parkinson\u2019s disease","volume":"27","author":"Papadopoulos","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neurobiolaging.2017.09.016","article-title":"Intercellular transfer of pathogenic \u03b1-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal","volume":"61","author":"Zhang","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","article-title":"Staging of brain pathology related to sporadic Parkinson\u2019s disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1007\/s00415-006-0396-4","article-title":"MRI derived brain atrophy in PSP and MSA-P","volume":"254","author":"Paviour","year":"2007","journal-title":"J. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Brettschneider, J., Irwin, D., Boluda, S., Byrne, M., Fang, L., Lee, E., Robinson, J., Suh, E., van Deerlin, V., and Toledo, J. (2016). Progression of \u03b1-synuclein pathology in multiple system atrophy of the cerebellar type. Neuropathol. Appl. Neurobiol.","DOI":"10.1111\/nan.12362"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1126\/science.1227157","article-title":"Pathological \u03b1-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice","volume":"338","author":"Luk","year":"2012","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1016\/j.celrep.2015.01.060","article-title":"Progressive Aggregation of \u03b1-Synuclein and Selective Degeneration of Lewy Inclusion-Bearing Neurons in a Mouse Model of Parkinsonism","volume":"10","author":"Osterberg","year":"2015","journal-title":"Cell. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.nbd.2015.06.003","article-title":"Intrastriatal injection of pre-formed mouse \u03b1-synuclein fibrils into rats triggers \u03b1-synuclein pathology and bilateral nigrostriatal degeneration","volume":"82","author":"Paumier","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/2051-5960-1-38","article-title":"Induction of CNS \u03b1-synuclein pathology by fibrillar and non-amyloidogenic recombinant \u03b1-synuclein","volume":"1","author":"Sacino","year":"2013","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1084\/jem.20160368","article-title":"Widespread transneuronal propagation of \u03b1-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson\u2019s disease","volume":"213","author":"Rey","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13010","DOI":"10.1073\/pnas.0903691106","article-title":"Inclusion formation and neuronal cell death through neuron-to-neuron transmission of \u03b1-synuclein","volume":"106","author":"Desplats","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3614","DOI":"10.1021\/pr0701512","article-title":"Identification of Proteins Involved in Microglial Endocytosis of \u03b1-Synuclein","volume":"6","author":"Liu","year":"2007","journal-title":"J. Proteome Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/j.biocel.2008.01.017","article-title":"Assembly-dependent endocytosis and clearance of extracellular \u03b1-synuclein","volume":"40","author":"Lee","year":"2008","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1750-1326-7-38","article-title":"Suppression of dynamin GTPase decreases \u03b1-synuclein uptake by neuronal and oligodendroglial cells: A potent therapeutic target for synucleinopathy","volume":"7","author":"Konno","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Mao, X., Ou, M., Karuppagounder, S., Kam, T., Yin, X., Xiong, Y., Ge, P., Umanah, G., Brahmachari, S., and Shin, J. (2016). Pathological \u03b1-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science, 353.","DOI":"10.1126\/science.aah3374"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0378-1119(98)00349-7","article-title":"Characterization of a 76 kDa endosomal, multispanning membrane protein that is highly conserved throughout evolution","volume":"216","author":"Diaz","year":"1998","journal-title":"Gene"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1126\/science.354.6315.956","article-title":"Rogue protein\u2019s partners offer hope in Parkinson\u2019s disease","volume":"354","author":"Wadman","year":"2016","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4240","DOI":"10.1523\/JNEUROSCI.5575-11.2012","article-title":"Deficiency of ATP13A2 Leads to Lysosomal Dysfunction, \u03b1-Synuclein Accumulation, and Neurotoxicity","volume":"32","author":"Usenovic","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1093\/brain\/awu002","article-title":"Glucocerebrosidase is shaking up the synucleinopathies","volume":"137","author":"Siebert","year":"2014","journal-title":"Brain"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ronzitti, G., Bucci, G., Emanuele, M., Leo, D., Sotnikova, T.D., Mus, L.V., Soubrane, C.H., Dallas, M.L., Thalhammer, A., and Cingolani, L.A. (2014). Exogenous \u03b1-synuclein decreases raft partitioning of Cav2.2 channels inducing dopamine release. J. Neurosci.","DOI":"10.1523\/JNEUROSCI.0608-14.2014"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"555","DOI":"10.2353\/ajpath.2008.070442","article-title":"Prion Diseases: From Protein to Cell Pathology","volume":"172","author":"Kovacs","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Goedert, M. (2015). Alzheimer\u2019s and Parkinson\u2019s diseases: The prion concept in relation to assembled A\u03b2, tau, and \u03b1-synuclein. Science, 349.","DOI":"10.1126\/science.1255555"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"E5308","DOI":"10.1073\/pnas.1514475112","article-title":"Evidence for \u03b1-synuclein prions causing multiple system atrophy in humans with parkinsonism","volume":"112","author":"Prusiner","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/nm1746","article-title":"Lewy bodies in grafted neurons in subjects with Parkinson\u2019s disease suggest host-to-graft disease propagation","volume":"14","author":"Li","year":"2008","journal-title":"Nat. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nm1747","article-title":"Lewy body\u2013like pathology in long-term embryonic nigral transplants in Parkinson\u2019s disease","volume":"14","author":"Kordower","year":"2008","journal-title":"Nat. Med."},{"key":"ref_62","first-page":"49","article-title":"Relationship of neighboring tissue and gliosis to \u03b1-synuclein pathology in a fetal transplant for Parkinson\u2019s disease","volume":"1","author":"Ahn","year":"2012","journal-title":"Am. J. Neurodegener. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0925-4439(00)00036-3","article-title":"Properties of NACP\/\u03b1-synuclein and its role in Alzheimer\u2019s disease","volume":"1502","author":"Iwai","year":"2000","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/nature15368","article-title":"Structure of the toxic core of \u03b1-synuclein from invisible crystals","volume":"525","author":"Rodriguez","year":"2015","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1750-1326-4-9","article-title":"\u03b1-Synuclein and neuronal cell death","volume":"4","author":"Cookson","year":"2009","journal-title":"Mol. Neurodegener."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/ana.24066","article-title":"Lewy body extracts from Parkinson disease brains trigger \u03b1-synuclein pathology and neurodegeneration in mice and monkeys","volume":"75","author":"Recasens","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41586-018-0104-4","article-title":"Cellular milieu imparts distinct pathological \u03b1-synuclein strains in \u03b1-synucleinopathies","volume":"557","author":"Peng","year":"2018","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1093\/brain\/awv114","article-title":"Expanding the spectrum of neuronal pathology in multiple system atrophy","volume":"138","author":"Cykowski","year":"2015","journal-title":"Brain"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1073\/pnas.1719369115","article-title":"Familial Parkinson\u2019s point mutation abolishes multiple system atrophy prion replication","volume":"115","author":"Woerman","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/neup.12243","article-title":"Accumulation of phosphorylated \u03b1-synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration","volume":"36","author":"Nakamura","year":"2016","journal-title":"Neuropathology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s00401-007-0244-3","article-title":"Development of \u03b1-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson\u2019s disease","volume":"114","author":"Braak","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00401-002-0655-0","article-title":"\u03b1-Synuclein pathology affecting Bergmann glia of the cerebellum in patients with \u03b1-synucleinopathies","volume":"105","author":"Piao","year":"2003","journal-title":"Acta Neuropathol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40478-018-0509-1","article-title":"Lack of pathogenic potential of peripheral \u03b1-synuclein aggregates from Parkinson\u2019s disease patients","volume":"6","author":"Recasens","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"E3138","DOI":"10.1073\/pnas.1301440110","article-title":"Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds","volume":"110","author":"Holmes","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Ihse, E., Yamakado, H., Wijk, X., Lawrence, R., Esko, J., and Masliah, E. (2017). Cellular Internalization of alpha-synuclien aggregagtes by cell surface heparin sulfate depends on aggregate conformation and cell type. Sci. Rep.","DOI":"10.1038\/s41598-017-08720-5"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Fellner, L., Buchinger, E., Brueck, D., Irschick, R., Wenning, G.K., and Stefanova, N. (2018). Limited effects of dysfunctional macroautophagy on the accumulation of extracellularly derived \u03b1-synuclein in oligodendroglia: Implications for MSA pathogenesis. BMC Neurosci., 19.","DOI":"10.1186\/s12868-018-0431-2"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00401-009-0619-8","article-title":"Astrocytes: Biology and pathology","volume":"119","author":"Sofroniew","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jns.2007.08.044","article-title":"Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders","volume":"267","author":"Mostert","year":"2008","journal-title":"J. Neurol. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1007\/s12035-016-9833-2","article-title":"Metabolic and Inflammatory Adaptation of Reactive Astrocytes: Role of PPARs","volume":"54","author":"Iglesias","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.mcn.2015.02.015","article-title":"The degree of astrocyte activation in multiple system atrophy is inversely proportional to the distance to \u03b1-synuclein inclusions","volume":"65","author":"Radford","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3389\/fncel.2015.00437","article-title":"Neuroinflammation in Multiple System Atrophy: Response to and Cause of \u03b1-Synuclein Aggregation","volume":"9","author":"Vieira","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/S0002-9440(10)62307-3","article-title":"Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy","volume":"166","author":"Stefanova","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"9262","DOI":"10.1074\/jbc.M109.081125","article-title":"Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies","volume":"285","author":"Lee","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1002\/glia.22437","article-title":"Toll-like receptor 4 is required for \u03b1-synuclein dependent activation of microglia and astroglia","volume":"61","author":"Fellner","year":"2013","journal-title":"Glia"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s12035-012-8340-3","article-title":"The Role of Glia in A-Synucleinopathies","volume":"47","author":"Fellner","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1080\/00207454.2017.1394851","article-title":"Alpha-synuclein levels in patients with multiple system atrophy: A meta-analysis","volume":"128","author":"Yang","year":"2018","journal-title":"Int. J. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2583","DOI":"10.1007\/s11064-015-1581-6","article-title":"The Glymphatic System: A Beginner\u2019s Guide","volume":"40","author":"Jessen","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Iliff, J., Wang, M., Liao, Y., Plogg, B., Peng, W., Gundersen, G., Benveniste, H., Vates, G., Deane, R., and Goldman, S. (2012). A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid \u03b2. Sci. Transl. Med., 4.","DOI":"10.1126\/scitranslmed.3003748"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"16180","DOI":"10.1523\/JNEUROSCI.3020-14.2014","article-title":"Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury","volume":"34","author":"Iliff","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Hoshi, A., Tsunoda, A., Tada, M., Nishizawa, M., Ugawa, Y., and Kakita, A. (2016). Expression of aquaporin 1 and aquaporin 4 in the temporal neocortex of patients with Parkinson\u2019s disease. Brain Pathol.","DOI":"10.1111\/bpa.12369"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"645","DOI":"10.3109\/00207454.2014.961454","article-title":"Cerebrospinal fluid \u03b1-synuclein as a biomarker for Parkinson\u2019s disease diagnosis: A systematic review and meta-analysis","volume":"125","author":"Gao","year":"2014","journal-title":"Int. J. Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Lundgaard, I., Lu, M., Yang, E., Peng, W., Mestre, H., Hitomi, E., Deane, R., and Nedergaard, M. (2016). Glymphatic clearance controls state-dependent changes in brain lactate concentration. J. Cereb. Blood Flow Metable.","DOI":"10.1177\/0271678X16661202"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/mds.23455","article-title":"Glia: Initiators and progressors of pathology in Parkinson\u2019s disease","volume":"26","author":"Halliday","year":"2011","journal-title":"Mov. Disord."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/nn.2923","article-title":"Heterogeneity of CNS myeloid cells and their roles in neurodegeneration","volume":"14","author":"Prinz","year":"2011","journal-title":"Nat. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Tang, Y., and Le, W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol. Neurobiol., 2015.","DOI":"10.1007\/s12035-014-9070-5"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/glia.10148","article-title":"Scavenger receptors in neurobiology and neuropathology: Their role on microglia and other cells of the nervous system","volume":"40","author":"Husemann","year":"2002","journal-title":"Glia"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1002\/glia.22409","article-title":"Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia","volume":"60","author":"Scheffel","year":"2012","journal-title":"Glia"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1152\/physrev.00011.2010","article-title":"Physiology of microglia","volume":"91","author":"Kettenmann","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"174","DOI":"10.2174\/187152710791012053","article-title":"Assessingactivationstates in microglia","volume":"9","author":"Colton","year":"2010","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.neuint.2013.04.007","article-title":"Microglia are the major source of TNF-a and TGF-b1 in post natal glial cultures;regulationbycytokines, lipopolysaccharide andvitronectin","volume":"63","author":"Milner","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1007\/s12035-013-8586-4","article-title":"Role and mechanism of microglial activation in iron-induced selective and progressive dopaminergic neurodegeneration","volume":"49","author":"Zhang","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1007\/s00415-009-5173-8","article-title":"Recent developments in multiple system atrophy","volume":"256","author":"Wenning","year":"2009","journal-title":"J. Neurol."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Kaufman, E., Hall, S., Surova, Y., Widner, H., Hansson, O., and Lindqvist, D. (2013). Proinflammatory Cytokines Are Elevated in Serum of Patients with Multiple System Atrophy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062354"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1212\/WNL.0000000000001807","article-title":"When DLB, PD, and PSP masquerade as MSA","volume":"85","author":"Koga","year":"2015","journal-title":"Neurology"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Daniele, S.G., B\u00e9raud, D., Davenport, C., Cheng, K., Yin, H., and Maguire-Zeiss, K.A. (2015). Activation of MyD88-dependent TLR1\/2 signaling by misfolded \u03b1-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal.","DOI":"10.1126\/scisignal.2005965"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cell.2015.08.069","article-title":"Lack of neuronal IFN-b-IFNAR causes lewy body-and parkinson\u2019s disease-like dementia","volume":"163","author":"Ejlerskov","year":"2015","journal-title":"Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.tox.2013.03.014","article-title":"Neonatal exposure tolipopolysaccharide enhances accumulation of a-synuclein aggregation and dopamine transporter proteinexpression in the substantia nigrainresponsestorotenonechallenge inlater life","volume":"308","author":"Tien","year":"2013","journal-title":"Toxicology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrn2038","article-title":"Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms","volume":"8","author":"Block","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_109","first-page":"80","article-title":"a-Synuclein alters toll-like receptor expression","volume":"5","author":"Twomey","year":"2011","journal-title":"Front. Neurosci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1007\/s11064-013-1020-5","article-title":"Screening of Toll-like receptors expression inmultiple system atrophy brains","volume":"38","author":"Brudek","year":"2013","journal-title":"Neurochem. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1242\/jcs.074088","article-title":"Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis","volume":"124","author":"Fitzner","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1523\/JNEUROSCI.1170-17.2017","article-title":"Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleinopathies","volume":"38","author":"Rockenstein","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/j.1471-4159.2009.06150.x","article-title":"On the mechanism of internalization of \u03b1-synuclein into microglia: Roles of ganglioside GM1 and lipid raft","volume":"110","author":"Park","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_114","first-page":"E1926","article-title":"\u03b1-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation","volume":"112","author":"Wang","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/j.neurobiolaging.2007.04.006","article-title":"Synuclein activates microglia in a model of Parkinson\u2019s disease","volume":"29","author":"Su","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1016\/j.ajpath.2011.04.013","article-title":"Toll-Like Receptor 4 Promotes \u03b1-Synuclein Clearance and Survival of Nigral Dopaminergic Neurons","volume":"179","author":"Stefanova","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1038\/ncomms2534","article-title":"Neuron-released oligomeric \u03b1-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia","volume":"4","author":"Kim","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Roodveldt, C., Labrador-Garrido, A., Gonzalez-Rey, E., Lachaud, C., Guilliams, T., Fernandez-Montesinos, R., Benitez-Rondan, A., Robledo, G., Hmadcha, A., and Delgado, M. (2013). Preconditioning of Microglia by \u03b1-Synuclein Strongly Affects the Response Induced by Toll-like Receptor (TLR) Stimulation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079160"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/nn.4132","article-title":"Depletion of microglia and inhibition of exosome synthesis halt tau propagation","volume":"18","author":"Asai","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Valdinocci, D., Radford, R.A., Siow, S.M., Chung, R.S., and Pountney, D.L. (2017). Potential Modes of Intercellular \u03b1-Synuclein Transmission. Int. J. Mol. Sci., 18.","DOI":"10.20944\/preprints201702.0020.v1"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.mcn.2018.04.006","article-title":"Epothilone D inhibits microglia-mediated spread of alpha-synuclein aggregates","volume":"89","author":"Valdinocci","year":"2018","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/srep00898","article-title":"Reichmann Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice","volume":"2","author":"Schwarz","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/jnc.12131","article-title":"Activity-dependent secretion of alpha-synuclein by enteric neurons","volume":"125","author":"Paillusson","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/jnc.12191","article-title":"Mind the gut: Secretion of \u03b1-synuclein by enteric neurons","volume":"125","author":"Grathwohl","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1007\/s12640-013-9420-5","article-title":"Alpha-Synuclein Transmission and Mitochondrial Toxicity in Primary Human Foetal Enteric Neurons in Vitro","volume":"25","author":"Braidy","year":"2014","journal-title":"Neurotox. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1586\/ern.09.115","article-title":"Olfactory dysfunction as a diagnostic marker for Parkinson\u2019s disease","volume":"9","author":"Haehner","year":"2009","journal-title":"Expert Rev. Neurother."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S1474-4422(06)70476-8","article-title":"Rapid-eye-movement sleep behaviour disorder as an early marker for an eurodegenerative disorder: A descriptive study","volume":"5","author":"Iranzo","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1007\/s00415-012-6801-2","article-title":"Gastrointestinal manifestations in Parkinson\u2019s disease: Prevalence and occurrence before motor symptoms","volume":"260","author":"Cersosimo","year":"2013","journal-title":"J. Neurol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1212\/WNL.42.4.726","article-title":"Gastrointestinal dysfunction in Parkinson\u2019s disease: Frequency and pathophysiology","volume":"42","author":"Edwards","year":"1992","journal-title":"Neurology"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"S87","DOI":"10.1016\/S1353-8020(09)70789-8","article-title":"Non-motor features of Parkinson\u2019s disease: Depression and dementia","volume":"15","author":"Reichmann","year":"2009","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.neulet.2005.11.012","article-title":"Gastric alpha-synuclein immunoreactive inclusions in Meissner\u2019s and Auerbach\u2018s plexuses in cases staged for Parkinson\u2019s disease-related brain pathology","volume":"396","author":"Braak","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jns.2011.04.016","article-title":"View point: Etiology in Parkinson\u2019s disease. Dual hit or spreading intoxication","volume":"310","author":"Reichmann","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00702-002-0808-2","article-title":"Idiopathic Parkinson\u2019s disease: Possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen","volume":"110","author":"Braak","year":"2003","journal-title":"J. Neural Transm. (Vienna)"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/j.1365-2990.2007.00874.x","article-title":"Parkinson\u2019s disease: A dual-hit hypothesis","volume":"33","author":"Hawkes","year":"2007","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/ana.24448","article-title":"Vagotomy and subsequent risk of Parkinson\u2019s disease","volume":"78","author":"Svensson","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1212\/WNL.0000000000003961","article-title":"Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study","volume":"88","author":"Liu","year":"2017","journal-title":"Neurology"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1002\/ana.24531","article-title":"Does vagotomy reduce the risk of Parkinson\u2019s disease?","volume":"78","author":"Tysnes","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1002\/mds.26605","article-title":"Neuropathological basis of nonmotor manifestations of Parkinson\u2019s disease","volume":"31","author":"Adler","year":"2016","journal-title":"Mov Disord."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/j.1365-2990.2008.00937.x","article-title":"The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson\u2019s disease","volume":"34","author":"Attems","year":"2008","journal-title":"Neuropathol. Appl Neurobiol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s00401-010-0664-3","article-title":"Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders","volume":"119","author":"Beach","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/j.1365-2990.2007.00923.x","article-title":"The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson\u2019s disease: A critical analysis of \u03b1-synuclein staging","volume":"34","author":"Kalaitzakis","year":"2008","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1007\/s00401-014-1343-6","article-title":"Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats","volume":"128","author":"Holmqvist","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00401-016-1661-y","article-title":"Brain-to-stomach transfer of \u03b1-synuclein via vagal preganglionic projections","volume":"133","author":"Ulusoy","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.cell.2016.11.018","article-title":"Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson\u2019s disease","volume":"167","author":"Sampson","year":"2016","journal-title":"Cell"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Pan-Montojo, F., Anichtchik, O., Dening, Y., Knels, L., Pursche, S., Jung, R., Jackson, S., Gille, G., Spillantini, M.G., Reichmann, H., and Funk, R.H. (2010). Progression of Parkinson\u2019s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS ONE, 5.","DOI":"10.1038\/npre.2010.3352.3"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"e183","DOI":"10.1111\/nmo.12070","article-title":"Effects of oral administration of rotenone on gastrointestinal functions in mice","volume":"25","author":"Tasselli","year":"2013","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/978-3-211-45295-0_41","article-title":"The rotenone model of parkinsonism\u2013the five years inspection","volume":"70","author":"Oertel","year":"2006","journal-title":"J. Neural Transm. Suppl."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"eaar5280","DOI":"10.1126\/scitranslmed.aar5280","article-title":"The vermiform appendix impacts the risk of developing Parkinson\u2019s disease","volume":"10","author":"Killinger","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.parkreldis.2012.04.020","article-title":"Analysis of colonic alpha-synuclein pathology in multiple system atrophy","volume":"18","author":"Pouclet","year":"2012","journal-title":"Park. Relat. Disord."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev-biochem-072711-163904","article-title":"Extracellular Chaperones and Proteostasis","volume":"82","author":"Wyatt","year":"2013","journal-title":"Annu. Rev. Biochem."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.neures.2010.04.008","article-title":"Extracellular neurosin degrades \u03b1-synuclein in cultured cells","volume":"67","author":"Tatebe","year":"2010","journal-title":"Neurosci. Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1093\/hmg\/ddg283","article-title":"Alpha-synuclein degradation by serine protease neurosin: Implication for pathogenesis of synucleinopathies","volume":"12","author":"Iwata","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neulet.2008.02.057","article-title":"Cleavage of normal and pathological forms of \u03b1-synuclein by neurosin in vitro","volume":"436","author":"Kasai","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"24862","DOI":"10.1074\/jbc.M112.348128","article-title":"Proteolytic Cleavage of Extracellular \u03b1-Synuclein by Plasmin","volume":"287","author":"Kim","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1159\/000097229","article-title":"Regulation of Matrix Metalloproteinase Expression in Astrocytes, Microglia and Neurons","volume":"3","author":"Gottschall","year":"1996","journal-title":"Neuroimmunomodulation"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"25216","DOI":"10.1074\/jbc.M503341200","article-title":"Proteolytic cleavage of extracellular secreted \u03b1-synuclein via matrix metalloproteinases","volume":"280","author":"Sung","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"4299","DOI":"10.4049\/jimmunol.180.6.4299","article-title":"Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages","volume":"180","author":"Vega","year":"2008","journal-title":"J. Immunol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"25497","DOI":"10.1074\/jbc.M400255200","article-title":"Hsp70 Reduces \u03b1-Synuclein Aggregation and Toxicity","volume":"279","author":"Klucken","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"9039","DOI":"10.1038\/s41598-017-08324-z","article-title":"The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress \u03b1-synuclein aggregation","volume":"7","author":"Aprile","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1523\/JNEUROSCI.6202-08.2009","article-title":"Rab11a and HSP90 regulate recycling of extracellular alpha-synuclein","volume":"29","author":"Liu","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0014-5793(02)02326-8","article-title":"Clusterin is an extracellular chaperone that specifically interacts with slowly aggregating proteins on their off-folding pathway","volume":"513","author":"Poon","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1096\/fj.06-7986com","article-title":"The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures","volume":"21","author":"Yerbury","year":"2007","journal-title":"FASEB J."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s00401-002-0546-4","article-title":"Clusterin\/apolipoprotein J is associated with cortical Lewy bodies: Immunohistochemical study in cases with alpha-synucleinopathies","volume":"104","author":"Sasaki","year":"2002","journal-title":"Acta Neuropathol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/s41591-018-0051-5","article-title":"Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson\u2019s disease","volume":"24","author":"Yun","year":"2018","journal-title":"Nat. Med."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1093\/brain\/awp282","article-title":"Brain alpha-synuclein accumulation in multiple system atrophy, Parkinson\u2019s disease and progressive supranuclear palsy: A comparative investigation","volume":"133","author":"Tong","year":"2010","journal-title":"Brain"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/4129\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:35:00Z","timestamp":1760196900000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/12\/4129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,19]]},"references-count":165,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["ijms19124129"],"URL":"https:\/\/doi.org\/10.3390\/ijms19124129","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,19]]}}}