Parkinson's disease (PD) is an age-related movement disorder characterized by a progressive degeneration of dopaminergic neurons in the midbrain. Although the presence of amyloid deposits of α-synuclein (α-syn) is the main pathological feature, PD brains also present a severe permanent inflammation, which largely contributes to neuropathology. Although α-syn has recently been implicated in this process, the molecular mechanisms underlying neuroinflammation remain unknown. In the present study, we investigated the ability of different α-syn aggregates to trigger inflammatory responses. We showed that α-syn induced inflammation through activation of Toll-like receptor 2 (TLR2) and the nucleotide oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome only when folded as amyloid fibrils. Oligomeric species, thought to be the primary species responsible for the disease, were surprisingly unable to trigger the same cascades. As neuroinflammation is a key player in PD pathology, these results put fibrils back to the fore and rekindles discussions about the primary toxic species contributing to the disease. Our data also suggest that the inflammatory properties of α-syn fibrils are linked to their intrinsic structure, most probably to their cross-β structure. Since fibrils of other amyloids induce similar immunological responses, we propose that the canonical fibril-specific cross-β structure represents a new generic motif recognized by the innate immune system.
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Research Article|
October 16 2015
Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease
Adelin Gustot;
Adelin Gustot
1
*Laboratory of Structure and Function of Biological Membranes, Université Libre de Bruxelles, Brussels 1050, Belgium
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José Ignacio Gallea;
José Ignacio Gallea
†Departamento de Química Biológica, Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC, CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina
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Rabia Sarroukh;
Rabia Sarroukh
*Laboratory of Structure and Function of Biological Membranes, Université Libre de Bruxelles, Brussels 1050, Belgium
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María Soledad Celej;
María Soledad Celej
†Departamento de Química Biológica, Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC, CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria, X5000HUA Córdoba, Argentina
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Jean-Marie Ruysschaert;
Jean-Marie Ruysschaert
*Laboratory of Structure and Function of Biological Membranes, Université Libre de Bruxelles, Brussels 1050, Belgium
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Vincent Raussens
Vincent Raussens
*Laboratory of Structure and Function of Biological Membranes, Université Libre de Bruxelles, Brussels 1050, Belgium
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Publisher: Portland Press Ltd
Received:
June 08 2015
Revision Received:
August 03 2015
Accepted:
August 13 2015
Accepted Manuscript online:
August 13 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2015 Authors; published by Portland Press Limited
2015
Biochem J (2015) 471 (3): 323–333.
Article history
Received:
June 08 2015
Revision Received:
August 03 2015
Accepted:
August 13 2015
Accepted Manuscript online:
August 13 2015
Citation
Adelin Gustot, José Ignacio Gallea, Rabia Sarroukh, María Soledad Celej, Jean-Marie Ruysschaert, Vincent Raussens; Amyloid fibrils are the molecular trigger of inflammation in Parkinson's disease. Biochem J 1 November 2015; 471 (3): 323–333. doi: https://doi.org/10.1042/BJ20150617
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