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

被引：111

作者：

Kim, Changyoun ^{[1
,2
]}

Rockenstein, Edward ^{[2
]}

Spencer, Brian ^{[2
]}

Kim, Hyung-Koo ^{[1
]}

Adame, Anthony ^{[2
]}

Trejo, Margarita ^{[2
]}

Stafa, Klodjan ^{[2
]}

Lee, He-Jin ^{[3
]}

Lee, Seung-Jae ^{[1
]}

Masliah, Eliezer ^{[2
]}

机构：

[1] Seoul Natl Univ, Coll Med, Dept Med, Neurosci Res Inst, Seoul 110799, South Korea

[2] Univ Calif San Diego, Sch Med, Dept Neurosci & Pathol, La Jolla, CA 92093 USA

[3] Konkuk Univ, Sch Med, Dept Anat, Seoul 143701, South Korea

来源：

CELL REPORTS | 2015年 / 13卷 / 04期

基金：

新加坡国家研究基金会;

关键词：

ALPHA-SYNUCLEIN; PARKINSONS-DISEASE; NEGATIVE REGULATOR; INHIBITION; PATHWAY; TARGET; NEUROPROTECTION; DEGRADATION; CLEARANCE; OUTGROWTH;

D O I：

10.1016/j.celrep.2015.09.044

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 alpha-synuclein, a protein aggregated in synucleinopathies, including in PD. Activation of TLR2 resulted in the accumulation of alpha-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 alpha-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.

引用

页码：771 / 782

页数：12