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, 28 (5), 547-553

Targeting Microglial and Neuronal Toll-like Receptor 2 in Synucleinopathies


Targeting Microglial and Neuronal Toll-like Receptor 2 in Synucleinopathies

Somin Kwon et al. Exp Neurobiol.


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.


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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