Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies.
Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies.
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DOI：
10.1371/journal.pone.0055375
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
de Bernard M
中科院分区：
文献类型：
--
作者：
Codolo G;Plotegher N;Pozzobon T;Brucale M;Tessari I;Bubacco L;de Bernard M
帕金森病（Parkinson's disease，PD）是最常见的神经退行性疾病之一。其特征在于大脑黑质部多巴胺能神经元的损失。另一个特征是在这些细胞中形成称为路易体（LB）的内含物，主要由纤维状α-突触核蛋白（αSyn）构成。这种蛋白质被认为是一组称为突触核蛋白病的神经退行性疾病（包括PD）病因学中的关键因素，但涉及的细胞和分子机制尚不完全清楚。已确定炎症过程在PD的发病机制和/或进展中起关键作用;此外，已知由神经元释放的聚集αSyn激活小胶质细胞以产生促炎介质，如IL-1β。IL-1β是最强的促炎细胞因子之一;它作为非活性介质产生，并且其成熟和活化需要炎性小体活化。特别地，NLRP 3炎性体被各种各样的刺激物激活，其中包括结晶和颗粒物质。在这项工作中，我们研究了由纤维状αSyn诱导的IL-1β产生参与炎性小体激活的可能性。我们证明了单体和纤维状αSyn通过TLR 2相互作用诱导IL-1β合成的能力;我们发现成熟细胞因子的分泌是纤维化蛋白的特性。此外，我们观察到IL-1β的分泌涉及NLRP 3炎性小体激活。后者依赖于纤维状αSyn的吞噬作用，随后增加ROS产生和组织蛋白酶B释放到胞质溶胶中。总之，我们的数据支持这样的观点，即可能由神经元变性释放的纤维状αSyn作为内源性触发物诱导PD中的强烈炎症反应。
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Another feature is represented by the formation in these cells of inclusions called Lewy bodies (LB), principally constituted by fibrillar α-synuclein (αSyn). This protein is considered a key element in the aetiology of a group of neurodegenerative disorders termed synucleinopathies, which include PD, but the cellular and molecular mechanisms involved are not completely clear. It is established that the inflammatory process plays a crucial role in the pathogenesis and/or progression of PD; moreover, it is known that aggregated αSyn, released by neurons, activates microglia cells to produce pro-inflammatory mediators, such as IL-1β. IL-1β is one of the strongest pro-inflammatory cytokines; it is produced as an inactive mediator, and its maturation and activation requires inflammasome activation. In particular, the NLRP3 inflammasome is activated by a wide variety of stimuli, among which are crystallized and particulate material. In this work, we investigated the possibility that IL-1β production, induced by fibrillar αSyn, is involved the inflammasome activation. We demonstrated the competence of monomeric and fibrillar αSyn to induce synthesis of IL-1β, through TLR2 interaction; we found that the secretion of the mature cytokine was a peculiarity of the fibrillated protein. Moreover, we observed that the secretion of IL-1β involves NLRP3 inflammasome activation. The latter relies on the phagocytosis of fibrillar αSyn, followed by increased ROS production and cathepsin B release into the cytosol. Taken together, our data support the notion that fibrillar αSyn, likely released by neuronal degeneration, acts as an endogenous trigger inducing a strong inflammatory response in PD.
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DOI：
10.1084/jem.20080421
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Getts DR;Terry RL;Getts MT;Müller M;Rana S;Shrestha B;Radford J;Van Rooijen N;Campbell IL;King NJ
通讯作者：
King NJ
影响因子：
6.1
作者：
Cintia Ferrari, Carina;Pott Godoy, Maria Clara;Juan Pitossi, Fernando
通讯作者：
Juan Pitossi, Fernando
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
4.3
作者：
Béraud D;Twomey M;Bloom B;Mittereder A;Ton V;Neitzke K;Chasovskikh S;Mhyre TR;Maguire-Zeiss KA
通讯作者：
Maguire-Zeiss KA
影响因子：
4.1
作者：
Beraud, Dawn;Maguire-Zeiss, Kathleen A
通讯作者：
Maguire-Zeiss, Kathleen A