title: Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons.
abstract: 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.
authors.affiliation: Division of Clinical Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. nadia.stefanova@i-med.ac.at
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Lisa
authors.initials: L
authors.lastname: Fellner
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000737:chemistry; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010641:Phenotype; D013378:Substantia Nigra / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D051197:Toll-Like Receptor 4; D051844:alpha-Synuclein