MMP13 Expression Is Increased Following Mutant α-Synuclein Exposure and Promotes Inflammatory Responses in Microglia.
MMP13 Expression Is Increased Following Mutant α-Synuclein Exposure and Promotes Inflammatory Responses in Microglia.
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突变 α-突触核蛋白暴露后 MMP13 表达增加，并促进小胶质细胞炎症反应。
DOI：
10.3389/fnins.2020.585544
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发表时间：
2020
影响因子：
4.3
通讯作者：
Maguire-Zeiss K
中科院分区：
文献类型：
--
作者：
Sánchez K;Maguire-Zeiss K
α-突触核蛋白是一种140个氨基酸的蛋白质，容易错误折叠，并与在帕金森病的散发和遗传形式中发现的路易体病理学有关。我们和其他人已经表明，野生型α-突触核蛋白是一种损伤相关的分子模式，通过toll样受体激活直接激发小胶质细胞的促炎反应。在这里，我们研究了寡聚突变体α-突触核蛋白（A53 T）对小胶质细胞形态和激活的直接影响。我们发现错误折叠的A53 T增加了变形细胞形态、NFκB核转位和原型促炎分子表达的定量测量。我们还证明A53 T增加了MMP 13的表达，MMP 13是一种重塑细胞外基质的基质金属蛋白酶。为了更好地理解MMP 13在突触核蛋白病中的作用，我们进一步表征了MMP 13在小胶质细胞信号传导中的作用。我们发现，暴露于MMP 13的小胶质细胞诱导形态学的变化，并促进TNFα和MMP 9的释放。值得注意的是，没有释放IL 1 β，表明参与MMP 13活化小胶质细胞的途径可能不同于A53 T途径。最后，MMP 13增加了CD 68的表达，这表明该MMP可能改变了溶酶体途径。总之，这项研究表明，突变体α-突触核蛋白直接诱导小胶质细胞中的促炎表型，其中包括MMP 13的表达。反过来，MMP 13直接改变小胶质细胞，支持多靶点治疗帕金森病患者的需要。
α-Synuclein is a 140-amino acid protein that readily misfolds and is associated with the Lewy body pathology found in sporadic and genetic forms of Parkinson's disease. We and others have shown that wild-type α-synuclein is a damage-associated molecular pattern that directly elicits a proinflammatory response in microglia through toll-like receptor activation. Here we investigated the direct effect of oligomeric mutant α-synuclein (A53T) on microglia morphology and activation. We found that misfolded A53T increased quantitative measures of amoeboid cell morphology, NFκB nuclear translocation and the expression of prototypical proinflammatory molecules. We also demonstrated that A53T increased expression of MMP13, a matrix metalloproteinase that remodels the extracellular matrix. To better understand the role of MMP13 in synucleinopathies, we further characterized the role of MMP13 in microglial signaling. We showed exposure of microglia to MMP13 induced a change in morphology and promoted the release of TNFα and MMP9. Notably, IL1β was not released indicating that the pathway involved in MMP13 activation of microglia may be different than the A53T pathway. Lastly, MMP13 increased the expression of CD68 suggesting that the lysosomal pathway might be altered by this MMP. Taken together this study shows that mutant α-synuclein directly induces a proinflammatory phenotype in microglia, which includes the expression of MMP13. In turn, MMP13 directly alters microglia supporting the need for multi-target therapies to treat Parkinson's disease patients.
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影响因子：
4.6
作者：
Brkic M;Balusu S;Libert C;Vandenbroucke RE
通讯作者：
Vandenbroucke RE
DOI：
10.1006/bbrc.1999.1551
发表时间：
1999-10-22
影响因子：
3.1
作者：
Bond, M;Baker, AH;Newby, AC
通讯作者：
Newby, AC
DOI：
10.1111/j.1460-9568.2010.07266.x
发表时间：
2010-07
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Feng LR;Federoff HJ;Vicini S;Maguire-Zeiss KA
通讯作者：
Maguire-Zeiss KA
影响因子：
4.6
作者：
Allen M;Ghosh S;Ahern GP;Villapol S;Maguire-Zeiss KA;Conant K
通讯作者：
Conant K
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