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Review
, 28 (5), 547-553

Targeting Microglial and Neuronal Toll-like Receptor 2 in Synucleinopathies

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Review

Targeting Microglial and Neuronal Toll-like Receptor 2 in Synucleinopathies

Somin Kwon et al. Exp Neurobiol.

Abstract

Synucleinopathies are neurodegenerative disorders characterized by the progressive accumulation of α-synuclein (α-syn) in neurons and glia and include Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this review, we consolidate our key findings and recent studies concerning the role of Toll-like receptor 2 (TLR2), a pattern recognition innate immune receptor, in the pathogenesis of synucleinopathies. First, we address the pathological interaction of α-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal α-syn accumulation by impairing autophagy, but also modulates α-syn transmission. Finally, we demonstrate that administration of a TLR2 functional inhibitor improves the neuropathology and behavioral deficits of a synucleinopathy mouse model. Altogether, we present TLR2 modulation as a promising immunotherapy for synucleinopathies.

Keywords: Immunotherapy; Neuroinflammation; Synucleinopathy; Toll-like receptor 2; α-synuclein.

Figures

Fig. 1
Fig. 1
Model of pathological TLR2 activation by neuron-released α-synuclein in neurons, astrocytes, and microglia. Under disease conditions, neurons release pathogenic α-syn into the extracellular space where they can interact with TLR2 on neighboring cells. In microglia and astrocytes, α-syn activates a TLR2 signaling cascade that induces a pro-inflammatory response, thereby generating a neurotoxic environment. α-syn can also interact with neuronal TLR2 to induce neurotoxic α-syn deposition by impairing autophagy. As such, TLR2 immunotherapy is a promising therapeutic strategy to prevent α-syn-mediated glial activation and cell-to-cell transmission of α-syn aggregates, ultimately ameliorating neurotoxic conditions in the synucleinopathy brain.

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References

    1. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–840. doi: 10.1038/42166. - DOI - PubMed
    1. McCann H, Stevens CH, Cartwright H, Halliday GM. α-Synucleinopathy phenotypes. Parkinsonism Relat Disord. 2014;20(Suppl 1):S62–S67. doi: 10.1016/S1353-8020(13)70017-8. - DOI - PubMed
    1. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science. 2000;287:1265–1269. doi: 10.1126/science.287.5456.1265. - DOI - PubMed
    1. Lashuel HA, Overk CR, Oueslati A, Masliah E. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14:38–48. doi: 10.1038/nrn3406. - DOI - PMC - PubMed
    1. Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci. 2005;25:6016–6024. doi: 10.1523/JNEUROSCI.0692-05.2005. - DOI - PMC - PubMed
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