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Cell Rep. 2015 Oct 27;13(4):771-782. doi: 10.1016/j.celrep.2015.09.044. Epub 2015 Oct 17.

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

Author information

1
Neuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea; Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
3
Neuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
4
Department of Anatomy, School of Medicine, Konkuk University, Seoul 143-701, Korea.
5
Neuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. Electronic address: sjlee66@snu.ac.kr.
6
Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: emasliah@ucsd.edu.

Abstract

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.

PMID:
26489461
PMCID:
PMC4752835
DOI:
10.1016/j.celrep.2015.09.044
[Indexed for MEDLINE]
Free PMC Article

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