Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy

Impaired autophagy has been implicated in many neurodegenerative diseases, such as Parkinson’s disease (PD), and might be responsible for deposition of aggregated proteins in neurons. However, little is known about how neuronal autophagy and clearance of aggregated proteins are regulated. Here, we show a role for Toll-like receptor 2 (TLR2), a pathogen-recognizing receptor in innate immunity, in regulation of neuronal autophagy and clearance of α-synuclein, a protein aggregated in synucleinopathies, including in PD. Activation of TLR2 resulted in the accumulation of α-synuclein aggregates in neurons as a result of inhibition of autophagic activity through regulation of the AKT/mTOR pathway. In contrast, inactivation of TLR2 resulted in autophagy activation and increased clearance of neuronal α-synuclein, and hence reduced neurodegeneration, in transgenic mice and in in vitro models. These results uncover roles of TLR2 in regulating neuronal autophagy and suggest that the TLR2 pathway may be targeted for autophagy activation strategies in treating neurodegenerative disorders. [Display omitted] •Activation of Toll-like receptor 2 antagonizes autophagy in neurons•TLR2 regulates neuronal autophagy via the AKT/mTOR pathway•Inhibition of the TLR2 pathway reduces neuronal α-synuclein aggregation•Inhibition of TLR2 rescues Lewy body disease models from neurodegeneration Impairment of neuronal autophagy is implicated in the pathogenesis of neurodegenerative proteinopathies. However, little is known about the extracellular cues that regulate neuronal autophagy. Kim et al. show that activation of Toll-like receptor 2 negatively regulates neuronal autophagy, and synucleinopathy lesions are rescued by antagonizing TLR2.