TY  - JOUR
AU  - Grozdanov, Veselin
AU  - Bousset, Luc
AU  - Hoffmeister, Meike
AU  - Bliederhaeuser, Corinna
AU  - Meier, Christoph
AU  - Madiona, Karine
AU  - Pieri, Laura
AU  - Kiechle, Martin
AU  - McLean, Pamela J
AU  - Kassubek, Jan
AU  - Behrends, Christian
AU  - Ludolph, Albert
AU  - Weishaupt, Jochen H
AU  - Melki, Ronald
AU  - Danzer, Karin M
TI  - Increased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease.
JO  - Annals of neurology
VL  - 86
IS  - 4
SN  - 1531-8249
CY  - Hoboken, NJ
PB  - Wiley-Blackwell
M1  - DZNE-2021-00965
SP  - 593 - 606
PY  - 2019
AB  - Excessive inflammation in the central nervous system (CNS) and the periphery can result in neurodegeneration and parkinsonism. Recent evidence suggests that immune responses in Parkinson disease patients are dysregulated, leading to an increased inflammatory reaction to unspecific triggers. Although α-synuclein pathology is the hallmark of Parkinson disease, it has not been investigated whether pathologic α-synuclein is a specific trigger for excessive inflammatory responses in Parkinson disease.We investigated the immune response of primary human monocytes and a microglial cell line to pathologic forms of α-synuclein by assessing cytokine release upon exposure.We show that pathologic α-synuclein (mutations, aggregation) results in a robust inflammatory activation of human monocytes and microglial BV2 cells. The activation is conformation- 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 α-synuclein is potentiated by extracellular vesicles, possibly by facilitating the uptake of α-synuclein. 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 α-synuclein. Furthermore, we demonstrate that α-synuclein pathology in the CNS is sufficient to induce the monocyte dysregulation in the periphery of a mouse model.Taken together, our data suggest that α-synuclein pathology and dysregulation of monocytes in Parkinson disease can act together to induce excessive inflammatory responses to α-synuclein. ANN NEUROL 2019;86:593-606.
KW  - Animals
KW  - Cells, Cultured
KW  - Cytokines: metabolism
KW  - Extracellular Vesicles: immunology
KW  - Humans
KW  - Inflammation: complications
KW  - Inflammation: metabolism
KW  - Mice
KW  - Mice, Transgenic
KW  - Microglia: metabolism
KW  - Monocytes: metabolism
KW  - Mutation
KW  - Parkinson Disease: immunology
KW  - Parkinson Disease: metabolism
KW  - alpha-Synuclein: adverse effects
KW  - alpha-Synuclein: genetics
KW  - Cytokines (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:31343083
DO  - DOI:10.1002/ana.25557
UR  - https://pub.dzne.de/record/155805
ER  -