Document Detail

Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons.
MedLine Citation:
PMID:  21801874     Owner:  NLM     Status:  MEDLINE    
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.
Nadia Stefanova; Lisa Fellner; Markus Reindl; Eliezer Masliah; Werner Poewe; Gregor K Wenning
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-06-14
Journal Detail:
Title:  The American journal of pathology     Volume:  179     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-01     Completed Date:  2012-04-09     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  954-63     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Division of Clinical Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
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MeSH Terms
Behavior, Animal
Cell Line, Tumor
DNA Primers / chemistry
Dopaminergic Neurons / metabolism*
Enzyme-Linked Immunosorbent Assay
Inflammation / metabolism
Mice, Inbred C57BL
Mice, Transgenic
Microscopy, Confocal / methods
Models, Biological
Neurodegenerative Diseases / metabolism
Substantia Nigra / metabolism*
Toll-Like Receptor 4 / metabolism*
alpha-Synuclein / metabolism*
Grant Support
AG022074/AG/NIA NIH HHS; AG18440/AG/NIA NIH HHS; AG5131/AG/NIA NIH HHS; F 4404-B19//Austrian Science Fund FWF; NS044233/NS/NINDS NIH HHS; NS057096/NS/NINDS NIH HHS; P 19989-B05//Austrian Science Fund FWF
Reg. No./Substance:
0/DNA Primers; 0/Toll-Like Receptor 4; 0/alpha-Synuclein

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