Abnormal aggregation of α-synuclein and sustained microglial activation are important contributors to the pathogenic processes in Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro, and in vivo approaches, we show that extracellular α-synuclein released from neuronal cells is an endogenous agonist for toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. TLR2 ligand activity of α-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric α-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.

A large number of putative cis-regulatory sequences have been annotated in the human genome, but the genes they control remain poorly defined. To bridge this gap, we generate maps of longrange chromatin interactions centered on 18,943 well-annotated promoters for protein-coding genes in 27 human cell/tissue types. We use this information to infer the target genes of 70,329 candidate regulatory elements, and suggest potential regulatory function for 27,325 non-coding sequence variants associated with 2,117 physiological traits and diseases. Integrative analysis of these promoter-centered interactome maps reveals widespread enhancer-like promoters involved in gene regulation and common molecular pathways underlying distinct groups of human traits and diseases.

SUMMARY 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 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 PD. Activation of TLR2 resulted in 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, hence reduced neurodegeneration, in transgenic mice and in in vitro models. These results uncover novel roles of TLR2 in regulating neuronal autophagy, and the TLR2 pathway may be targeted for the autophagy activation strategies in treating neurodegenerative disorders.