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抑制钙蛋白酶可预防器官型脑片培养物中锰诱导的细胞损伤和α-突触核蛋白寡聚化。

Inhibition of calpain prevents manganese-induced cell injury and alpha-synuclein oligomerization in organotypic brain slice cultures.

作者信息

Xu Bin, Liu Wei, Deng Yu, Yang Tian-Yao, Feng Shu, Xu Zhao-Fa

机构信息

Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China.

出版信息

PLoS One. 2015 Mar 10;10(3):e0119205. doi: 10.1371/journal.pone.0119205. eCollection 2015.

DOI:10.1371/journal.pone.0119205
PMID:25756858
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4355489/
Abstract

Overexposure to manganese has been known to promote alpha-synuclein oligomerization and enhance cellular toxicity. However, the exact mechanism of Mn-induced alpha-synuclein oligomerization is unclear. To explore whether alpha-synuclein oligomerization was associated with the cleavage of alpha-synuclein by calpain, we made a rat brain slice model of manganism and pretreated slices with calpain inhibitor II, a cell-permeable peptide that restricts the activity of calpain. After slices were treated with 400 μM Mn for 24 h, there were significant increases in the percentage of apoptotic cells, lactate dehydrogenase release, intracellular [Ca2+]i, calpain activity, and the mRNA and protein expression of calpain 1 and alpha-synuclein. Moreover, the number of C- and N-terminal fragments of alpha-synuclein and the amount of alpha-synuclein oligomerization also increased. These results also showed that calpain inhibitor II pretreatment could reduce Mn-induced nerve cell injury and alpha-synuclein oligomerization. Additionally, there was a significant decrease in the number of C- and N-terminal fragments of alpha-synuclein in calpain inhibitor II-pretreated slices. These findings revealed that Mn induced the cleavage of alpha-synuclein protein via overactivation of calpain and subsequent alpha-synuclein oligomerization in cultured slices. Moreover, the cleavage of alpha-synuclein by calpain 1 is an important signaling event in Mn-induced alpha-synuclein oligomerization.

摘要

已知过度暴露于锰会促进α-突触核蛋白寡聚化并增强细胞毒性。然而，锰诱导α-突触核蛋白寡聚化的确切机制尚不清楚。为了探究α-突触核蛋白寡聚化是否与钙蛋白酶对α-突触核蛋白的切割有关，我们制作了锰中毒大鼠脑片模型，并用钙蛋白酶抑制剂II（一种可限制钙蛋白酶活性的细胞渗透性肽）对脑片进行预处理。在用400μM锰处理脑片24小时后，凋亡细胞百分比、乳酸脱氢酶释放、细胞内[Ca2+]i、钙蛋白酶活性以及钙蛋白酶1和α-突触核蛋白的mRNA和蛋白质表达均显著增加。此外，α-突触核蛋白的C端和N端片段数量以及α-突触核蛋白寡聚化程度也增加。这些结果还表明，钙蛋白酶抑制剂II预处理可减轻锰诱导的神经细胞损伤和α-突触核蛋白寡聚化。此外，在经钙蛋白酶抑制剂II预处理的脑片中，α-突触核蛋白的C端和N端片段数量显著减少。这些发现揭示，锰通过钙蛋白酶的过度激活诱导α-突触核蛋白蛋白的切割以及随后在培养脑片中的α-突触核蛋白寡聚化。此外，钙蛋白酶1对α-突触核蛋白的切割是锰诱导α-突触核蛋白寡聚化中的一个重要信号事件。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/eeaae5d74571/pone.0119205.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/e62329746c99/pone.0119205.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/f54eb09808e2/pone.0119205.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/cd42c9804790/pone.0119205.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/c2ae1c40e896/pone.0119205.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/485adc1a53d3/pone.0119205.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/890b1383152b/pone.0119205.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/eeaae5d74571/pone.0119205.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/e62329746c99/pone.0119205.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/f54eb09808e2/pone.0119205.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/cd42c9804790/pone.0119205.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/c2ae1c40e896/pone.0119205.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/485adc1a53d3/pone.0119205.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/890b1383152b/pone.0119205.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/85a1/4355489/eeaae5d74571/pone.0119205.g007.jpg

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