Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice.
Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice.
复制标题
炎性体抑制可防止小鼠α-突触核蛋白病理学和多巴胺能神经退行性变化。
DOI：
10.1126/scitranslmed.aah4066
复制
发表时间：
2018-10-31
影响因子：
17.1
通讯作者：
Woodruff TM
中科院分区：
文献类型：
--
作者：
Gordon R;Albornoz EA;Christie DC;Langley MR;Kumar V;Mantovani S;Robertson AAB;Butler MS;Rowe DB;O'Neill LA;Kanthasamy AG;Schroder K;Cooper MA;Woodruff TM
帕金森病 (PD) 的特点是黑质中多巴胺能神经元的严重丧失，并伴有慢性神经炎症、线粒体功能障碍以及路易体形式的富含 α-突触核蛋白的蛋白质聚集体的广泛积累。然而，α-突触核蛋白病理学和多巴胺能神经元死亡与慢性小胶质细胞神经炎症之间的联系机制尚未完全阐明。我们发现，小胶质细胞 NLR 家族包含热蛋白结构域 3 (NLRP3) 炎性体的激活是在缺乏 α-突触核蛋白聚集体的情况下由纤维状 α-突触核蛋白和多巴胺能变性触发的常见途径。在 PD 患者大脑黑质和多种临床前 PD 模型中，裂解的 caspase-1 和含有 C 末端 caspase 募集结构域 (ASC) 的炎性体接头蛋白凋亡相关斑点样蛋白升高。小鼠小胶质细胞中的纤维状 α-突触核蛋白激活 NLRP3，导致 NLRP3 炎性体延迟但强烈的激活，导致细胞外白细胞介素 1β 和 ASC 在没有细胞焦亡的情况下释放。纳摩尔剂量的小分子 NLRP3 抑制剂 MCC950 可消除小鼠小胶质细胞中纤维状 α-突触核蛋白介导的炎症小体激活和细胞外 ASC 释放。此外，在多种啮齿类PD模型中口服MCC950可抑制炎症小体激活，并有效减轻运动缺陷、黑质纹状体多巴胺能变性和α-突触核蛋白聚集体的积累。这些发现表明，小胶质细胞 NLRP3 可能是神经炎症的持续来源，可驱动进行性多巴胺能神经病理学，并强调 NLRP3 作为 PD 疾病缓解治疗的潜在靶点。口服脑渗透性 NLRP3 抑制剂对帕金森病临床前模型具有保护作用
Parkinson’s disease (PD) is characterized by a profound loss of dopaminergic neurons in the substantia nigra, accompanied by chronic neuroinflammation, mitochondrial dysfunction, and widespread accumulation of α-synuclein-rich protein aggregates in the form of Lewy bodies. However, the mechanisms linking α-synuclein pathology and dopaminergic neuronal death to chronic microglial neuroinflammation have not been completely elucidated. We show that activation of the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome is a common pathway triggered by both fibrillar α-synuclein and dopaminergic degeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 and the inflammasome adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) were elevated in the substantia nigra of the brains of patients with PD and in multiple preclinical PD models. NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in a delayed but robust activation of the NLRP3 inflammasome leading to extracellular interleukin-1β and ASC release in the absence of pyroptosis. Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolished fibrillar α-synuclein-mediated inflammasome activation in mouse microglial cells and extracellular ASC release. Furthermore, oral administration of MCC950 in multiple rodent PD models inhibited inflammasome activation and effectively mitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be a sustained source of neuroinflammation that could drive progressive dopaminergic neuropathology and highlight NLRP3 as a potential target for disease-modifying treatments for PD. Oral treatment with a brain-penetrant NLRP3 inhibitor has protective effects in preclinical models of Parkinson’s disease
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
15.1
作者：
Saresella M;La Rosa F;Piancone F;Zoppis M;Marventano I;Calabrese E;Rainone V;Nemni R;Mancuso R;Clerici M
通讯作者：
Clerici M
影响因子：
30.5
作者：
Baroja-Mazo, Alberto;Martin-Sanchez, Fatima;Pelegrin, Pablo
通讯作者：
Pelegrin, Pablo
适配器 ASC 具有传播炎症的细胞外活性和“prionoid”活性。
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
3.7
作者：
Codolo G;Plotegher N;Pozzobon T;Brucale M;Tessari I;Bubacco L;de Bernard M
通讯作者：
de Bernard M