Toll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies


Type
Article
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Authors
Horne, CB 
Williams-Gray, CH 
Abstract

Toll-like receptors (TLRs) are pattern recognition receptors which mediate an inflammatory response upon the detection of specific molecular patterns found on foreign organisms and on endogenous damage-related molecules. These receptors play a major role in the activation of microglia, the innate immune cells of the CNS, and are also expressed in peripheral tissues, including blood mononuclear cells and the gut. It is well established that immune activation, in both the brain and periphery, is a feature of Parkinson’s disease as well as other α-synucleinopathies. Aggregated forms of α-synuclein can act as ligands for TLRs (particularly TLR2 and TLR4), and hence these receptors may play a critical role in mediating a detrimental immune response to this protein, as well as other inflammatory signals in Parkinson’s and related α-synucleinopathies. In this review, the potential role of TLRs in contributing to the progression of these disorders is discussed. Existing evidence comes predominantly from studies in in vitro and in vivo models, as well as analyses of postmortem human brain tissue and pre-clinical studies of TLR inhibitors. This evidence is evaluated in detail, and the potential for therapeutic intervention in α-synucleinopathies through TLR inhibition is discussed.

Description
Keywords
Animals, Brain, Humans, Microglia, Parkinson Disease, Parkinsonian Disorders, Synucleinopathies, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptors, alpha-Synuclein
Journal Title
Brain, Behavior, and Immunity
Conference Name
Journal ISSN
0889-1591
1090-2139
Volume Title
Publisher
Elsevier BV
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MR/R007446/1)
The authors are supported by the NIHR Cambridge Biomedical Research Centre Dementia Theme (146281) and the Rosetrees Trust (M369-F1). AK is supported by the Onassis Foundation and the Alborada Trust. CWG is funded by an MRC Clinician Scientist Fellowship (Grant: MR/R007446/1).