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 s...

Full description

Bibliographic Details
Main Authors:	Changyoun Kim, Edward Rockenstein, Brian Spencer, Hyung-Koo Kim, Anthony Adame, Margarita Trejo, Klodjan Stafa, He-Jin Lee, Seung-Jae Lee, Eliezer Masliah
Format:	Article
Language:	English
Published:	Elsevier 2015-10-01
Series:	Cell Reports
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211124715010694

id	doaj-96826f1f78fd40a5b0a85a3fc791beab
record_format	Article
spelling	doaj-96826f1f78fd40a5b0a85a3fc791beab2020-11-25T01:38:53ZengElsevierCell Reports2211-12472015-10-0113477178210.1016/j.celrep.2015.09.044Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating AutophagyChangyoun Kim0Edward Rockenstein1Brian Spencer2Hyung-Koo Kim3Anthony Adame4Margarita Trejo5Klodjan Stafa6He-Jin Lee7Seung-Jae Lee8Eliezer Masliah9Neuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, KoreaDepartment of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USADepartment of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USANeuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, KoreaDepartment of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USADepartment of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USADepartment of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USADepartment of Anatomy, School of Medicine, Konkuk University, Seoul 143-701, KoreaNeuroscience Research Institute, Department of Medicine, Seoul National University College of Medicine, Seoul 110-799, KoreaDepartment of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USAImpaired 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.http://www.sciencedirect.com/science/article/pii/S2211124715010694
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Changyoun Kim Edward Rockenstein Brian Spencer Hyung-Koo Kim Anthony Adame Margarita Trejo Klodjan Stafa He-Jin Lee Seung-Jae Lee Eliezer Masliah
spellingShingle	Changyoun Kim Edward Rockenstein Brian Spencer Hyung-Koo Kim Anthony Adame Margarita Trejo Klodjan Stafa He-Jin Lee Seung-Jae Lee Eliezer Masliah Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy Cell Reports
author_facet	Changyoun Kim Edward Rockenstein Brian Spencer Hyung-Koo Kim Anthony Adame Margarita Trejo Klodjan Stafa He-Jin Lee Seung-Jae Lee Eliezer Masliah
author_sort	Changyoun Kim
title	Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy
title_short	Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy
title_full	Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy
title_fullStr	Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy
title_full_unstemmed	Antagonizing Neuronal Toll-like Receptor 2 Prevents Synucleinopathy by Activating Autophagy
title_sort	antagonizing neuronal toll-like receptor 2 prevents synucleinopathy by activating autophagy
publisher	Elsevier
series	Cell Reports
issn	2211-1247
publishDate	2015-10-01
description	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.
url	http://www.sciencedirect.com/science/article/pii/S2211124715010694
work_keys_str_mv	AT changyounkim antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT edwardrockenstein antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT brianspencer antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT hyungkookim antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT anthonyadame antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT margaritatrejo antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT klodjanstafa antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT hejinlee antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT seungjaelee antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy AT eliezermasliah antagonizingneuronaltolllikereceptor2preventssynucleinopathybyactivatingautophagy
_version_	1725051730415058944

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

Similar Items