Increased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease

Veselin Grozdanov, Luc Bousset, Meike Hoffmeister, Corinna Bliederhaeuser, Christoph Meier, Karine Madiona, Laura Pieri, Martin Kiechle, Pamela J McLean, Jan Kassubek, Christian Behrends, Albert C. Ludolph, Jochen H. Weishaupt, Ronald Melki, Karin M. Danzer

Research output: Contribution to journalArticle

Abstract

Objective: 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. Methods: 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. Results: 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. Interpretation: 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.

Original languageEnglish (US)
JournalAnnals of neurology
DOIs
StateAccepted/In press - Jan 1 2019

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Synucleins
Parkinson Disease
Monocytes
Pathology
Central Nervous System
Mutation
Parkinsonian Disorders

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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Grozdanov, V., Bousset, L., Hoffmeister, M., Bliederhaeuser, C., Meier, C., Madiona, K., ... Danzer, K. M. (Accepted/In press). Increased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease. Annals of neurology. https://doi.org/10.1002/ana.25557

Increased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease. / Grozdanov, Veselin; Bousset, Luc; Hoffmeister, Meike; Bliederhaeuser, Corinna; Meier, Christoph; Madiona, Karine; Pieri, Laura; Kiechle, Martin; McLean, Pamela J; Kassubek, Jan; Behrends, Christian; Ludolph, Albert C.; Weishaupt, Jochen H.; Melki, Ronald; Danzer, Karin M.

In: Annals of neurology, 01.01.2019.

Research output: Contribution to journalArticle

Grozdanov, V, Bousset, L, Hoffmeister, M, Bliederhaeuser, C, Meier, C, Madiona, K, Pieri, L, Kiechle, M, McLean, PJ, Kassubek, J, Behrends, C, Ludolph, AC, Weishaupt, JH, Melki, R & Danzer, KM 2019, 'Increased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease', Annals of neurology. https://doi.org/10.1002/ana.25557
Grozdanov V, Bousset L, Hoffmeister M, Bliederhaeuser C, Meier C, Madiona K et al. Increased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease. Annals of neurology. 2019 Jan 1. https://doi.org/10.1002/ana.25557
Grozdanov, Veselin ; Bousset, Luc ; Hoffmeister, Meike ; Bliederhaeuser, Corinna ; Meier, Christoph ; Madiona, Karine ; Pieri, Laura ; Kiechle, Martin ; McLean, Pamela J ; Kassubek, Jan ; Behrends, Christian ; Ludolph, Albert C. ; Weishaupt, Jochen H. ; Melki, Ronald ; Danzer, Karin M. / Increased Immune Activation by Pathologic α-Synuclein in Parkinson's Disease. In: Annals of neurology. 2019.
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AU - Bousset, Luc

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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 C.

AU - Weishaupt, Jochen H.

AU - Melki, Ronald

AU - Danzer, Karin M.

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N2 - Objective: 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. Methods: 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. Results: 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. Interpretation: 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.

AB - Objective: 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. Methods: 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. Results: 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. Interpretation: 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.

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