All ETDs from UAB

Advisory Committee Chair

David G Standaert

Advisory Committee Members

Scott R Barnum

Etty Benveniste

Robert P Kimberly

Andrew B West

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The protein alpha-synuclein (α-SYN), which is found in the Lewy bodies of dopaminergic (DA) neurons in the substantia nigra (SN), has an important role in the pathogenesis of Parkinson's disease (PD). Fcγ receptors (FcγR) are proteins present on the surface of microglia, which bind immunoglobulin G (IgG) and other ligands. Our studies in an AAV-synuclein mouse model of PD showed that over-abundance of α-SYN triggered the expression of NF-κB p65, and led to microglial activation and DA neurodegeneration; however, in mice deficient of gamma chain subunit of the Fc receptors (FcγR-/- mice), α-SYN-induced NF-κB signaling was blocked, while microglial activation and DA neurodegeneration were attenuated. In order to study whether α-SYN interacts directly with microglia, we treated the primary microglia of wild-type (WT) and FcγR-/- mice with aggregated human α-SYN in vitro. We found that α-SYN was taken up by both WT and FcγR-/- microglia though with different internalization patterns. α-SYN-induced nuclear accumulation of NF-κB p65 and downstream chemokine expression in WT microglia were blocked in FcγR-/- ones. Moreover, we hypothesize that excess α-SYN causes further microgliosis through major histocompatibility complex-II (MHC-II) antigen presentation to T-lymphocytes, and this process is FcγR-dependent. To test this hypothesis, in vivo we selectively over-expressed human α-SYN in the SN of WT and FcγR-/- mice, and in vitro, we performed T-cell co-culture with WT and FcγR-/- microglia. Over-abundance of α-SYN in mouse SN triggered IgG deposition and vigorous MHC-II expression in the brain, and these immune responses were markedly attenuated in FcγR-/- mice. α-SYN-treated microglia-T cell co-culture produced increased pro-inflammatory molecules and this elevated cytokine expression was blocked with FcγR-/- microglia. Our results suggest that the humoral adaptive immune response triggered by excess α-SYN plays a causative role in microglial activation through IgG-FcγR interaction. This involves NF-κB signaling, and leads to DA neurodegeneration. To further activate microglia, α-SYN-induced microglial MHC-II antigen presentation to CD4+ T-lymphocytes is a crucial step, and FcγRs are indispensable in this process. Therefore, blocking either FcγR signaling or specific intracellular events downstream of FcγR-IgG interaction, such as NF-κB activation or MHC-II antigen presentation may be viable therapeutic strategies in PD.

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