Targeting Microglial and Neuronal Toll-like Receptor 2 in Synucleinopathies

Synudeinopalhies are neurodegeneralive disorders characterized by the progressive accumulation of alpha-synuclein (alpha-syn) in neurons and glia and include Parkinson 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 alpha-syn with microglial TLR2 and its neurotoxic inflammatory effects. Then, we show that neuronal TLR2 activation not only induces abnormal a-syn accumulation by impairing autophagy but also modulates alpha-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.