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Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets.

ABSTRACT: Microglial inflammatory neuroregulatory activities affect the tempo of nigrostriatal degeneration during Parkinson's disease (PD). Such activities are induced, in part, by misfolded, nitrated alpha-synuclein (N-alpha-syn) within Lewy bodies released from dying or dead dopaminergic neurons. Such pathobiological events initiate innate and adaptive immune responses affecting neurodegeneration. We posit that the neurobiological activities of activated microglia are affected by cell-protein and cell-cell contacts, in that microglial interactions with N-alpha-syn and CD4(+) T cells substantively alter the microglial proteome. This leads to alterations in cell homeostatic functions and disease. CD4(+)CD25(+) regulatory T cells suppress N-alpha-syn microglial-induced reactive oxygen species and NF-kappaB activation by modulating redox-active enzymes, cell migration, phagocytosis, and bioenergetic protein expression and cell function. In contrast, CD4(+)CD25(-) effector T cells exacerbate microglial inflammation and induce putative neurotoxic responses. These data support the importance of adaptive immunity in the regulation of Parkinson's disease-associated microglial inflammation.

SUBMITTER: Reynolds AD

PROVIDER: S-EPMC2659470 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets.

Reynolds Ashley D AD Stone David K DK Mosley R Lee RL Gendelman Howard E HE

Journal of immunology (Baltimore, Md. : 1950) 20090401 7

Microglial inflammatory neuroregulatory activities affect the tempo of nigrostriatal degeneration during Parkinson's disease (PD). Such activities are induced, in part, by misfolded, nitrated alpha-synuclein (N-alpha-syn) within Lewy bodies released from dying or dead dopaminergic neurons. Such pathobiological events initiate innate and adaptive immune responses affecting neurodegeneration. We posit that the neurobiological activities of activated microglia are affected by cell-protein and cell- ...[more]

PMID: 19299711

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Project description:Accumulation of neuronal α-synuclein is a prominent feature in Parkinson's disease. More recently, such abnormal protein aggregation has been reported to spread from cell to cell and exosomes are considered as important mediators. The focus of such research, however, has been primarily in neurons. Given the increasing recognition of the importance of non-cell autonomous-mediated neurotoxicity, it is critical to investigate the contribution of glia to α-synuclein aggregation and spread. Microglia are the primary phagocytes in the brain and have been well-documented as inducers of neuroinflammation. How and to what extent microglia and their exosomes impact α-synuclein pathology has not been well delineated. We report here that when treated with human α-synuclein preformed fibrils, exosomes containing α-synuclein released by microglia are fully capable of inducing protein aggregation in the recipient neurons. Additionally, when combined with microglial proinflammatory cytokines, these exosomes further increased protein aggregation in neurons. Inhibition of exosome synthesis in microglia reduced α-synuclein transmission. The in vivo significance of these exosomes was demonstrated by stereotaxic injection of exosomes isolated from α-synuclein preformed fibrils treated microglia into the mouse striatum. Phosphorylated α-synuclein was observed in multiple brain regions consistent with their neuronal connectivity. These animals also exhibited neurodegeneration in the nigrostriatal pathway in a time-dependent manner. Depleting microglia in vivo dramatically suppressed the transmission of α-synuclein after stereotaxic injection of preformed fibrils. Mechanistically, we report here that α-synuclein preformed fibrils impaired autophagy flux by upregulating PELI1, which in turn, resulted in degradation of LAMP2 in activated microglia. More importantly, by purifying microglia/macrophage derived exosomes in the CSF of Parkinson's disease patients, we confirmed the presence of α-synuclein oligomer in CD11b+ exosomes, which were able to induce α-synuclein aggregation in neurons, further supporting the translational aspect of this study. Taken together, our study supports the view that microglial exosomes contribute to the progression of α-synuclein pathology and therefore, they may serve as a promising therapeutic target for Parkinson's disease.

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Dataset Information

Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets.

Publications

Nitrated {alpha}-synuclein-induced alterations in microglial immunity are regulated by CD4+ T cell subsets.

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