Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8684738 | Experimental Neurology | 2018 | 9 Pages |
Abstract
Accumulation of alpha-synuclein (α-syn) in the central nervous system (CNS) is a core feature of Parkinson disease (PD) that leads to activation of the innate immune system, production of inflammatory cytokines and chemokines, and subsequent neurodegeneration. Here, we used heterozygous reporter knock-in mice in which the first exons of the fractalkine receptor (CX3CR1) and of the C-C chemokine receptor type 2 (CCR2) are replaced with fluorescent reporters to study the role of resident microglia (CX3CR1 +) and infiltrating peripheral monocytes (CCR2 +), respectively, in the CNS. We used an α-syn mouse model induced by viral over-expression of α-syn. We find that in vivo, expression of full-length human α-syn induces robust infiltration of pro-inflammatory CCR2 + peripheral monocytes into the substantia nigra. Genetic deletion of CCR2 prevents α-syn induced monocyte entry, attenuates MHCII expression and blocks the subsequent degeneration of dopaminergic neurons. These results demonstrate that extravasation of pro-inflammatory peripheral monocytes into the CNS plays a key role in neurodegeneration in this model of PD synucleinopathy, and suggest that peripheral monocytes may be a target of neuroprotective therapies for human PD.
Keywords
CCL2Parkinson disease (PD)RFPMHCIIC-C chemokine receptor type 2CCR2CX3CR1AAV2MPTPα-SynGFP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineSNpcAlpha-synucleinmajor histocompatibility complex IIParkinson diseasesubstantia nigra pars compactatyrosine hydroxylaseCNScentral nervous systemgenome wide association studiesGWASMonocytesMicrogliagreen fluorescent proteinred fluorescent proteinfractalkine receptor
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Authors
Ashley S. Harms, Aaron D. Thome, Zhaoqi Yan, Aubrey M. Schonhoff, Gregory P. Williams, Xinru Li, Yudong Liu, Hongwei Qin, Etty N. Benveniste, David G. Standaert,