Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson's Disease.
Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson's Disease.
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DOI：
10.1021/acs.jproteome.0c01002
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发表时间：
2021-07-02
影响因子：
4.4
通讯作者：
Ko HS
中科院分区：
文献类型：
--
作者：
Ma SX;Seo BA;Kim D;Xiong Y;Kwon SH;Brahmachari S;Kim S;Kam TI;Nirujogi RS;Kwon SH;Dawson VL;Dawson TM;Pandey A;Na CH;Ko HS
帕金森病（PD）是第二常见的神经退行性疾病，其导致运动功能障碍，并最终导致认知障碍。α-Synuclein蛋白是PD病理生理学的中心蛋白，但其潜在的病理机制尚不清楚。为了理解α-突触核蛋白如何成为PD病理学的基础，已经开发了具有α-突触核蛋白过表达的各种PD小鼠模型。然而，缺乏对这些小鼠模型的脑蛋白质组的系统分析。本研究通过注射α-synuclein preformed fibrils（PFF）和诱导人A53 T α-synuclein过表达两种方法建立PD小鼠模型，探讨两种不同类型PD小鼠模型的共同通路。为了更准确地定量小鼠脑蛋白质组，采用稳定同位素标记法对哺乳动物脑蛋白质组进行定量。我们从两种小鼠模型中共鉴定了8355种蛋白质;从注射α-突触核蛋白的PFF小鼠和人A53 T α-突触核蛋白转基因小鼠中分别鉴定了约6800和约7200种蛋白质。通过对两种PD小鼠模型共有的差异表达蛋白的途径分析，发现与对照动物相比，PD小鼠中的补体和凝血级联途径富集。值得注意的是，一项验证研究表明，纹状体内α-突触核蛋白PFF注射小鼠的腹侧中脑中补体成分3（C3）阳性星形胶质细胞增加，星形胶质细胞分泌的C3可诱导多巴胺能神经元变性。这是第一项通过对两种复杂的PD小鼠模型进行蛋白质组分析来强调补体和凝血途径在PD发病机制中的重要性的研究。
Parkinson’s disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and, eventually, cognitive impairment. α-Synuclein protein is known as a central protein to the pathophysiology of PD, but the underlying pathological mechanism still remains to be elucidated. In an effort to understand how α-synuclein underlies the pathology of PD, various PD mouse models with α-synuclein overexpression have been developed. However, systemic analysis of the brain proteome of those mouse models is lacking. In this study, we established two mouse models of PD by injecting α-synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T α-synuclein to investigate common pathways in the two different types of the PD mouse models. For more accurate quantification of mouse brain proteome, the proteins were quantified using the method of stable isotope labeling with amino acids in mammals. We identified a total of 8355 proteins from the two mouse models; ~6800 and ~7200 proteins from α-synuclein PFF-injected mice and human A53T α-synuclein transgenic mice, respectively. Through pathway analysis of the differentially expressed proteins common to both PD mouse models, it was discovered that the complement and coagulation cascade pathways were enriched in the PD mice compared to control animals. Notably, a validation study demonstrated that complement component 3 (C3)-positive astrocytes were increased in the ventral midbrain of the intrastriatal α-synuclein PFF-injected mice and C3 secreted from astrocytes could induce the degeneration of dopaminergic neurons. This is the first study that highlights the significance of the complement and coagulation pathways in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.
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影响因子：
82.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
影响因子：
2.5
作者：
Iseki, E;Marui, W;Kosaka, K
通讯作者：
Kosaka, K
影响因子：
7.1
作者：
Hu WT;Watts KD;Tailor P;Nguyen TP;Howell JC;Lee RC;Seyfried NT;Gearing M;Hales CM;Levey AI;Lah JJ;Lee EK;Alzheimer’s Disease Neuro-Imaging Initiative
通讯作者：
Alzheimer’s Disease Neuro-Imaging Initiative
中脑多巴胺能神经元中与帕金森氏病相关的突变体α-突触核蛋白的有条件表达会导致进行性神经变性和转录因子核受体相关的降解1。
DOI：
10.1523/jneurosci.1731-12.2012
发表时间：
2012-07-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lin X;Parisiadou L;Sgobio C;Liu G;Yu J;Sun L;Shim H;Gu XL;Luo J;Long CX;Ding J;Mateo Y;Sullivan PH;Wu LG;Goldstein DS;Lovinger D;Cai H
通讯作者：
Cai H