Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons

Am J Pathol. 2011 Aug;179(2):954-63. doi: 10.1016/j.ajpath.2011.04.013. Epub 2011 Jun 14.


Toll-like receptors (TLRs) mediate innate immunity, and their dysregulation may play a role in α-synucleinopathies, such as Parkinson's disease or multiple system atrophy (MSA). The aim of this study was to define the role of TLR4 in α-synuclein-linked neurodegeneration. Ablation of TLR4 in a transgenic mouse model of MSA with oligodendroglial α-synuclein overexpression augmented motor disability and enhanced loss of nigrostriatal dopaminergic neurons. These changes were associated with increased brain levels of α-synuclein linked to disturbed TLR4-mediated microglial phagocytosis of α-synuclein. Furthermore, tumor necrosis factor-α levels were increased in the midbrain and associated with a proinflammatory astroglial response. Our data suggest that TLR4 ablation impairs the phagocytic response of microglia to α-synuclein and enhances neurodegeneration in a transgenic MSA mouse model. The study supports TLR4 signaling as innate neuroprotective mechanism acting through clearance of α-synuclein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Cell Line, Tumor
  • DNA Primers / chemistry
  • Dopaminergic Neurons / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Inflammation / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal / methods
  • Models, Biological
  • Neurodegenerative Diseases / metabolism
  • Phenotype
  • Substantia Nigra / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • alpha-Synuclein / metabolism*


  • DNA Primers
  • Toll-Like Receptor 4
  • alpha-Synuclein