Low copper and high manganese levels in prion protein plaques.
Low copper and high manganese levels in prion protein plaques.
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DOI：
10.3390/v5020654
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发表时间：
2013-02-11
期刊：
影响因子：
--
通讯作者：
McKenzie D
中科院分区：
文献类型：
--
作者：
Johnson CJ;Gilbert PU;Abrecht M;Baldwin KL;Russell RE;Pedersen JA;Aiken JM;McKenzie D
富含异常折叠形式朊病毒蛋白的聚集体的积累是传染性海绵状脑病（TSE）引起的神经变性的特征。斑块形成和神经变性的分子触发因素仍然未知，但对 TSE 感染的脑匀浆和富含异常朊病毒蛋白的制剂的分析表明，铜水平降低和锰水平升高与疾病相关。本研究的目的是：（1）评估健康和感染 TSE 的叙利亚仓鼠脑匀浆中的铜和锰水平； (2) 使用同步辐射的 X 射线光电子发射显微镜 (X-PEEM) 确定是否可以绘制 TSE 感染脑组织中这些金属的分布图； (3)使用X-PEEM原位评估朊病毒斑块中铜和锰的相对含量。与其他 TSE 和物种的研究一致，我们发现仓鼠模型中与疾病相关的大脑铜水平降低，锰水平升高。我们还发现脑干中这些金属的原位水平足以通过 X-PEEM 进行成像。使用直接相邻组织切片中的免疫标记朊病毒斑来识别通过 X-PEEM 成像的区域，我们发现朊病毒斑中铜锰失调存在统计学上显着的关系：铜被耗尽，而锰被富集。这些数据提供了朊病毒斑改变 TSE 感染中枢神经系统局部过渡金属分布的证据。
Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1) assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2) determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM) with synchrotron radiation; and (3) use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.
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