Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease.

Academic Article

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.
  • Published In

    Keywords

  • C-C chemokine receptor type 2 (CCR2), Fractalkine receptor (CX3CR1) Major histocompatibility complex II (MHCII), Microglia, Monocytes, Parkinson disease (PD), α-syn (alpha-synuclein), Animals, Disease Models, Animal, Inflammation, Intermediate Filament Proteins, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Nerve Degeneration, Parkinson Disease, Secondary
  • Digital Object Identifier (doi)

    Author List

  • Harms AS; Thome AD; Yan Z; Schonhoff AM; Williams GP; Li X; Liu Y; Qin H; Benveniste EN; Standaert DG
  • Start Page

  • 179
  • End Page

  • 187
  • Volume

  • 300