Exp Neurobiol 2016; 25(3): 113-119
Published online June 30, 2016
© The Korean Society for Brain and Neural Sciences
Changyoun Kim1,2, He-Jin Lee3, Eliezer Masliah2 and Seung-Jae Lee1*
1Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea, 2Departments of Neurosciences and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA, 3Department of Anatomy, School of Medicine, Konkuk University, Seoul 05030, Korea
Correspondence to: *To whom correspondence should be addressed.
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Synucleinopathies are a collection of neurological diseases that are characterized by deposition of α-synuclein aggregates in neurons and glia. These diseases include Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. Although it has been increasingly clear that α-synuclein is implicated in the pathogenesis of PD and other synucleinopathies, the precise mechanism underlying the disease process remains to be unraveled. The past studies on how α-synuclein exerts pathogenic actions have focused on its direct, cell-autonomous neurotoxic effects. However, recent findings suggested that there might be indirect, non-cell-autonomous pathways, perhaps through the changes in glial cells, for the pathogenic actions of this protein. Here, we present evidence that α-synuclein can cause neurodegeneration through a non-cell-autonomous manner. We show that α-synuclein can be secreted from neurons and induces inflammatory responses in microglia, which in turn secreted neurotoxic agents into the media causing neurodegeneration. The neurotoxic response of microglia was mediated by activation of toll-like receptor 2 (TLR2), a receptor for neuron-derived α-synuclein. This work suggests that TLR2 is the key molecule that mediates non-cell-autonomous neurotoxic effects of α-synuclein, hence a candidate for the therapeutic target.
Keywords: Parkinson’s disease, α-synuclein, Toll-like receptor 2, Microglia, Neurodegeneration