Toll-like receptor 2 is increased in neurons in Parkinson's disease brain and may contribute to alpha-synuclein pathology

被引:194
作者
Dzamko, Nicolas [1 ,2 ]
Gysbers, Amanda [1 ]
Perera, Gayathri [1 ]
Bahar, Anita [1 ]
Shankar, Amrita [1 ,2 ]
Gao, Jianqun [1 ,2 ]
Fu, YuHong [1 ,2 ]
Halliday, Glenda M. [1 ,2 ]
机构
[1] Neurosci Res Australia, Barker St, Randwick, NSW 2031, Australia
[2] Univ NSW, Sch Med Sci, Sydney, NSW 2052, Australia
基金
英国医学研究理事会;
关键词
Parkinson's disease; Toll-like receptor; alpha-Synuclein; Autophagy; Inflammation; ACTIVATES MICROGLIA; CEREBROSPINAL-FLUID; SUBSTANTIA-NIGRA; INFLAMMATION; RAPAMYCIN; PROTEIN; PROGRESSION; INNATE; MODEL; TLR2;
D O I
10.1007/s00401-016-1648-8
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Inflammation is likely a key contributor to the pathogenesis of Parkinson's disease (PD), a progressively debilitating neurodegenerative disease that is accompanied by a pathological accumulation of the alpha-synuclein protein in a staged manner through the brain. What leads to the accumulation of alpha-synuclein in PD and how this relates to inflammatory pathways, however, is not entirely clear. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation and, in particular, TLR2 is increasingly being implicated in PD. We have, therefore, examined the expression of TLR2 in postmortem brain tissue from PD patients and matched controls. We confirm that TLR2 is increased in PD brain, and find that levels of TLR2 correlate with the accumulation of pathological alpha-synuclein. TLR2 was expressed on neurons as well as microglia; however, the neuronal rather than glial expression of TLR2 was significantly increased in PD brain in accordance with disease staging, and TLR2 was strongly localized to alpha-synuclein positive Lewy bodies. In cell culture, activation of neuronal TLR2 induced an inflammatory response, including the secretion of inflammatory cytokines and microglial-activating chemokines, as well as the production of reactive oxygen species. Moreover, activation of neuronal TLR2 increased levels of endogenous alpha-synuclein protein, which was in turn associated with increased levels of the autophagy/lysosomal pathway marker p62. Finally, promoting autophagy with rapamycin or pharmacological inhibition of the TLR2 signaling pathway prevented the TLR2-mediated increase in alpha-synuclein in neuronal cell cultures. These results implicate neuronal TLR2 expression in human PD pathogenesis. In particular, the increased expression of TLR2 on neurons may provide new insight into disease pathogenesis and/or options for therapeutic intervention.
引用
收藏
页码:303 / 319
页数:17
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