Glial innate immunity generated by non-aggregated alpha-synuclein in mouse: differences between wild-type and Parkinson's disease-linked mutants |
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Authors: | Roodveldt Cintia Labrador-Garrido Adahir Gonzalez-Rey Elena Fernandez-Montesinos Rafael Caro Marta Lachaud Christian C Waudby Christopher A Delgado Mario Dobson Christopher M Pozo David |
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Institution: | CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Consejo Superior de Investigaciones Científicos, University of Seville-UPO-Junta de Andalucia, Seville, Spain. |
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Abstract: | BackgroundParkinson''s disease (PD) is a progressive neurodegenerative disorder
characterized pathologically by the presence in the brain of intracellular
protein inclusions highly enriched in aggregated alpha-synuclein
(α-Syn). Although it has been established that progression of the
disease is accompanied by sustained activation of microglia, the underlying
molecules and factors involved in these immune-triggered mechanisms remain
largely unexplored. Lately, accumulating evidence has shown the presence of
extracellular α-Syn both in its aggregated and monomeric forms in
cerebrospinal fluid and blood plasma. However, the effect of extracellular
α-Syn on cellular activation and immune mediators, as well as the
impact of familial PD-linked α-Syn mutants on this stimulation, are
still largely unknown.Methods and FindingsIn this work, we have compared the activation profiles of non-aggregated,
extracellular wild-type and PD-linked mutant α-Syn variants on
primary glial and microglial cell cultures. After stimulation of cells with
α-Syn, we measured the release of Th1- and Th2- type cytokines as
well as IP-10/CXCL10, RANTES/CCL5, MCP-1/CCL2 and MIP-1α/CCL3
chemokines. Contrary to what had been observed using cell lines or for the
case of aggregated α-Syn, we found strong differences in the immune
response generated by wild-type α-Syn and the familial PD mutants
(A30P, E46K and A53T).ConclusionsThese findings might contribute to explain the differences in the onset and
progression of this highly debilitating disease, which could be of value in
the development of rational approaches towards effective control of immune
responses that are associated with PD. |
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