Fig. 8

Model for TLR2 immunotherapy ameliorates neurodegeneration in synucleinopathy. In disease condition, TLR2 mediates neurotoxicity. In neuron, i) TLR2 induces pathological internalization of extracellular α-synuclein into neuron and ii) extracellular α-synuclein activates neuronal TLR2 which results in mTOR-mediated autophagy inhibition. Thus, neuronal TLR2 induces neurotoxic α-synuclein accumulation. In astrocyte, iii) TLR2 increased abnormal α-synuclein accumulation which leads astroglial activation and iv) extracellular α-synuclein activates astroglial TLR2 signaling cascade through NFκB/p38 MAPK which results in neurotoxic astroglial responses such as pro-inflammatory cytokine expression and induction of reactive microglia recruiting chemokines. Therefore, TLR2 immunotherapy ameliorates α-synuclein-mediated neurotoxicity via inhibition of 1) TLR2-mediated neuronal α-synuclein internalization, 2) activation of neuronal autophagy via TLR2-mTOR signaling cascade, 3) inhibition of TLR2-mediated astroglial responses, and 4) reduction of astroglial α-synuclein accumulation. Thereby, TLR2 immunotherapy might be a novel therapeutic strategy for synucleinopathy