| First Author | Thome AD | Year | 2015 |
| Journal | PLoS One | Volume | 10 |
| Issue | 10 | Pages | e0140566 |
| PubMed ID | 26469270 | Mgi Jnum | J:243783 |
| Mgi Id | MGI:5912562 | Doi | 10.1371/journal.pone.0140566 |
| Citation | Thome AD, et al. (2015) Fractalkine Signaling Regulates the Inflammatory Response in an alpha-Synuclein Model of Parkinson Disease. PLoS One 10(10):e0140566 |
| abstractText | BACKGROUND: Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (alpha-syn). Increasing evidence points to inflammation as a chief mediator; however, the role of alpha-syn in triggering and sustaining inflammation remains unclear. In models of Alzheimer's disease (AD), multiple sclerosis (MS) and neurotoxin models of PD, the chemokine CX3CL1 (fractalkine) and its receptor (CX3CR1) have important roles in modulating neuroinflammation. METHODS: To examine the role of fractalkine signaling in alpha-syn-induced-neuroinflammation and neurodegeneration, we used an in vivo mouse model in which human alpha-syn is overexpressed by an adeno associated viral vector serotype 2 (AAV2) and in vitro phagocytosis and protein internalization assays with primary microglia treated with aggregated alpha-syn. RESULTS: We observed that loss of CX3CR1 expression led to a reduced inflammatory response, with reduced IgG deposition and expression of MHCII 4 weeks post-transduction. Six months post transduction, AAV2 mediated overexpression of alpha-syn leads to loss of dopaminergic neurons, and this loss was not exacerbated in animals with deletion of CX3CR1. To determine the mechanism by which CX3CR1affects inflammatory responses in alpha-syn-induced inflammation, phagocytosis was assessed using a fluorescent microsphere assay as well as by microglial uptake of aggregated alpha-syn. CX3CR1-/- microglia showed reduced uptake of fluorescent beads and aggregated alpha-syn. CONCLUSION: Our results suggest that one mechanism by which CX3CR1-/- attenuates inflammation is at the level of phagocytosis of aggregated alpha-syn by microglia. These data implicate fractalkine signaling as a potential therapeutic target for regulating inflammatory response in alpha-syn models PD. |
