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Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although \u03b1\u2010synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic \u03b1\u2010synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of \u03b1\u2010synuclein by assessing cytokine release upon exposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We show that pathologic \u03b1\u2010synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation\u2010 dependent, with increasing fibrillation and early onset mutations having the strongest effect on immune activation. We also found that activation of immune cells by extracellular \u03b1\u2010synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of \u03b1\u2010synuclein. Blood extracellular vesicles from Parkinson disease patients induce a stronger activation of monocytes than blood extracellular vesicles from healthy controls. Most importantly, monocytes from Parkinson disease patients are dysregulated and hyperactive in response to stimulation with pathologic \u03b1\u2010synuclein. Furthermore, we demonstrate that \u03b1\u2010synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Taken together, our data suggest that \u03b1\u2010synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to \u03b1\u2010synuclein. ANN NEUROL 2019;86:593\u2013606<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.25557","type":"journal-article","created":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T06:39:44Z","timestamp":1564036784000},"page":"593-606","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":161,"title":["Increased Immune Activation by Pathologic \u03b1\u2010Synuclein in Parkinson's Disease"],"prefix":"10.1002","volume":"86","author":[{"given":"Veselin","family":"Grozdanov","sequence":"first","affiliation":[{"name":"Department of Neurology Ulm University  Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Bousset","sequence":"additional","affiliation":[{"name":"Molecular Imaging Research Center, Francois Jacob Institute, Alternative Energies and Atomic Energy Commission, and Laboratory of Neurodegenerative Diseases National Center for Scientific Research  Fontenay\u2010Aux\u2010Roses 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