Glial Innate Immunity Generated by Non-Aggregated Alpha-Synuclein in Mouse: Differences between Wild-type and Parkinson's Disease-Linked Mutants

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.

Alpha-Synuclein and the Immune Response in Parkinson’s Disease

“…Even though a study using monocytic THP-1 cell line (Klegeris et al, 2008) had shown modest increases in IL-1 and TNF- secretion levels after stimulation with A30P, A53T, or E46K Syn mutants compared to the Wt protein, there is a lack of a comprehensive study of the effect exerted by non-aggregated Syn, performed with primary cell cultures. With this in mind, we analysed the cytokine release profile of primary microglial cultures -which represesnts a more comparable physiological environment-after stimulation with Wt or the PD-linked Syn mutants (Roodveldt et al, 2010). Indeed, we found remarkable differences between the Syn variants in the interleukin and chemokine release profiles and significant effects on the microglial phagocytic capacity (Roodveldt et al, 2010).…”

“…A few investigations that explore the effects of non-aggregated Syn on the cytokine release profile of potentially relevant cells have been recently done using monocytic (Klegeris et al, 2008) or macrophage (Lee et al, 2009b) cell lines, and primary astrocyte (Klegeris et al, 2006) or microglial (Roodveldt et al, 2010;Su et al, 2009;Su et al, 2008) cultures. Indeed, we have observed a strong innate immune response in primary glial and microglial cell cultures elicited by exogenous, non-aggregated Syn (Roodveldt et al, 2010). Interestingly, a comparative study using unmodified aSyn has recently shown that exogenous non-aggregated Syn induces higher TNF-, IL-1 and ROS release levels than aggregated Syn in microglia (Lee et al, 2010).…”

“…With this in mind, we analysed the cytokine release profile of primary microglial cultures -which represesnts a more comparable physiological environment-after stimulation with Wt or the PD-linked Syn mutants (Roodveldt et al, 2010). Indeed, we found remarkable differences between the Syn variants in the interleukin and chemokine release profiles and significant effects on the microglial phagocytic capacity (Roodveldt et al, 2010). In particular, we observed marked differences in IL-6 and IL-1pro-inflammtory cytokines, IL-10 immunoregulatory cytokine, as well as IP-10/CXCL10, RANTES/CCL5, MCP-1/CCL2 and MIP-1/CCL3 chemokines release levels.…”

Dysfunction of two lysosome degradation pathways of α-synuclein in Parkinson’s disease: potential therapeutic targets?

“…This suggests other cells in the brain such as astroglia [11,17] . Moreover, unlike the endocytotic internalization of α-syn fibrils and oligomers, monomeric α-syn enters the cell through membrane transport (a non-endocytotic mechanism), and its internalization is much faster than that of the aggregated form [12] .…”

“…Missense mutation, overexpression, or gene damage of α-syn undoubtedly increases the probability of its aggregation. All of these conditions appear to contribute at least partially to familial and sporadic PD [17,18] .…”