α-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration.
α-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration.
复制标题
DOI：
10.1186/s40478-017-0494-9
复制
发表时间：
2017-11-21
影响因子：
7.1
通讯作者：
West AB
中科院分区：
文献类型：
--
作者：
Harms AS;Delic V;Thome AD;Bryant N;Liu Z;Chandra S;Jurkuvenaite A;West AB
主要组织相容性复合体II （MHCII）编码基因（HLA-DR）的遗传变异增加了帕金森病（PD）的风险，并且大脑中表达MHCII的免疫细胞的积累与α-突触核蛋白包涵体相关。然而，关于正在进行的神经退行性变中MHCII细胞募集的时间，以及PD脑中表达MHCII的细胞类型，一直难以理解。最近的研究表明，将α-突触核蛋白短原纤维注入大鼠黑质致密部（SNpc），可诱导SNpc神经元进进式包络形成，并最终扩散到纹状体的棘突神经元。在此，我们发现α-突触核蛋白原纤维在大脑中迅速引发持续的MHCII反应。相比之下，等量的单体α-突触核蛋白不能诱导MHCII或持续的小胶质细胞激活，这与我们在原发性小胶质细胞中的结果一致。流式细胞术和免疫组织化学分析显示，表达mhcii的细胞既包括常驻小胶质细胞，也包括来自外周的细胞，包括单核细胞、巨噬细胞和淋巴细胞。随着时间的推移，SNpc中的α-突触核蛋白纤维暴露会导致轴突损失以及纹状体中的单核细胞募集。虽然纹状体中的这些单核细胞最初缺乏MHCII表达，但α-突触核蛋白包涵体后来在附近的刺状投射神经元中形成，MHCII表达变得强劲。综上所述，在大鼠α-突触核蛋白原纤维模型中，外周免疫细胞募集发生在神经变性之前，小胶质细胞、单核细胞和巨噬细胞都参与了MHCII的表达。本文的在线版本（10.1186/s40478-017-0494-9）包含补充材料，可供授权用户使用。
Genetic variation in a major histocompatibility complex II (MHCII)-encoding gene (HLA-DR) increases risk for Parkinson disease (PD), and the accumulation of MHCII-expressing immune cells in the brain correlates with α-synuclein inclusions. However, the timing of MHCII-cell recruitment with respect to ongoing neurodegeneration, and the types of cells that express MHCII in the PD brain, has been difficult to understand. Recent studies show that the injection of short α-synuclein fibrils into the rat substantia nigra pars compacta (SNpc) induces progressive inclusion formation in SNpc neurons that eventually spread to spiny projection neurons in the striatum. Herein, we find that α-synuclein fibrils rapidly provoke a persistent MHCII response in the brain. In contrast, equivalent amounts of monomeric α-synuclein fail to induce MHCII or persistent microglial activation, consistent with our results in primary microglia. Flow cytometry and immunohistochemical analyses reveal that MHCII-expressing cells are composed of both resident microglia as well as cells from the periphery that include monocytes, macrophages, and lymphocytes. Over time, α-Synuclein fibril exposures in the SNpc causes both axon loss as well as monocyte recruitment in the striatum. While these monocytes in the striatum initially lack MHCII expression, α-synuclein inclusions later form in nearby spiny projection neurons and MHCII expression becomes robust. In summary, in the rat α-synuclein fibril model, peripheral immune cell recruitment occurs prior to neurodegeneration and microglia, monocytes and macrophages all contribute to MHCII expression. The online version of this article (10.1186/s40478-017-0494-9) contains supplementary material, which is available to authorized users.
登录
查看更多内容
DOI：
10.3233/jpd-150691
发表时间：
2016
期刊：
Journal of Parkinson's disease
影响因子：
--
作者：
Bousset L;Brundin P;Böckmann A;Meier B;Melki R
通讯作者：
Melki R
影响因子：
30.5
作者：
Goldmann T;Wieghofer P;Jordão MJ;Prutek F;Hagemeyer N;Frenzel K;Amann L;Staszewski O;Kierdorf K;Krueger M;Locatelli G;Hochgerner H;Zeiser R;Epelman S;Geissmann F;Priller J;Rossi FM;Bechmann I;Kerschensteiner M;Linnarsson S;Jung S;Prinz M
通讯作者：
Prinz M
影响因子：
21.3
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
通讯作者：
Iwatsubo, T
DOI：
10.4049/jimmunol.1100421
发表时间：
2012-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mizutani M;Pino PA;Saederup N;Charo IF;Ransohoff RM;Cardona AE
通讯作者：
Cardona AE
DOI：
10.1126/science.1227157
发表时间：
2012-11-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Luk KC;Kehm V;Carroll J;Zhang B;O'Brien P;Trojanowski JQ;Lee VM
通讯作者：
Lee VM