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.
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.
Changyoun
C
Kim
Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Edward
E
Rockenstein
Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Brian
B
Spencer
Neuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
Hyung-Koo
HK
Kim
Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Anthony
A
Adame
Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Margarita
M
Trejo
Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Klodjan
K
Stafa
Department of Anatomy, School of Medicine, Konkuk University, Seoul 143-701, Korea.
He-Jin
HJ
Lee
Neuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea. Electronic address: sjlee66@snu.ac.kr.
Seung-Jae
SJ
Lee
Department of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: emasliah@ucsd.edu.
Eliezer
E
Masliah
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000517:prevention & control; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
D051195:Toll-Like Receptor 2; D051844:alpha-Synuclein; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases