Friedreich's ataxia causes redistribution of iron, copper, and zinc in the dentate nucleus.
Friedreich's ataxia causes redistribution of iron, copper, and zinc in the dentate nucleus.
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弗里德里希（Friedreich）的共济失调导致齿状核中铁，铜和锌的重新分布。
DOI：
10.1007/s12311-012-0383-5
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发表时间：
2012-12
期刊：
影响因子：
3.5
通讯作者：
Feustel, Paul J.
中科院分区：
文献类型：
--
作者：
Koeppen, Arnulf H.;Ramirez, R. Liane;Yu, Devin;Collins, Sarah E.;Qian, Jiang;Parsons, Patrick J.;Yang, Karl X.;Chen, Zewu;Mazurkiewicz, Joseph E.;Feustel, Paul J.
关键词：
弗里德赖希共济失调 (FRDA) 导致齿状核 (DN) 大神经元选择性萎缩。高铁（Fe）浓度和未能从受影响的脑组织中清除金属是病变进展的潜在危险因素。 DN 还含有相对较高含量的铜 (Cu) 和锌 (Zn)，但这些金属在 FRDA 中的重要性尚未确定。本报告描述了 10 名 FRDA 患者和 13 名对照者的聚乙二醇二甲基亚砜 (PEG/DMSO) 包埋的 DN 中的非破坏性定量 X 射线荧光 (XRF) 和 Fe、Cu 和 Zn 的“映射”。 Fe 荧光主要来自肺门白质，而 Cu 和 Zn 在 DN 灰质中达到峰值水平。尽管 FRDA 中 DN 崩溃了，但 Fe 信号峰值的位置没有改变。相比之下，铜和锌区域变宽，并与富铁区域广泛重叠。最大金属浓度与正常值没有差异（以微克每毫升固体 PEG/DMSO 为平均值±标准差）：Fe 正常值，364±117，FRDA，344±159； Cu 正常值，33 ± 13，FRDA，33 ± 18； Zn正常，32±16，FRDA，33±19。从PEG/DMSO中回收组织并转移到石蜡中，用于与神经元特异性烯醇化酶（NSE）、谷氨酸脱羧酶（GAD）和铁蛋白的免疫组织化学相匹配。 NSE 和 GAD 反应产物证实了神经元萎缩和赘瘤变性，与异常扩散的铜和锌区域一致。铁蛋白免疫组织化学与 Fe XRF 图谱相匹配，揭示了 DN 门少突胶质细胞中最丰富的反应产物。在 FRDA 中，这些细胞比正常细胞更小、数量更多。在 FRDA 的萎缩性 DN 灰质中，抗铁蛋白标记的大部分是肥大的小胶质细胞。 Cu 反应蛋白 Cu,Zn 超氧化物歧化酶和 Cu++ 转运 ATP 酶 α 肽的免疫组织化学和免疫荧光未检测到 FRDA 中对 Cu 重新分布的特异性反应。相比之下，金属硫蛋白 (MT) 阳性突起比正常情况更丰富，并导致 DN 的神经胶质增生。 MT、MT-1/2 和脑特异性 MT-3 的亚型仅与神经胶质纤维酸性蛋白存在有限的共定位。结果表明，MT 可以针对 FRDA 中的内源性 Cu 和 Zn 毒性提供有效的保护，类似于全铁蛋白中 Fe 的神经保护性隔离。
Friedreich's ataxia (FRDA) causes selective atrophy of the large neurons of the dentate nucleus (DN). High iron (Fe) concentration and failure to clear the metal from the affected brain tissue are potential risk factors in the progression of the lesion. The DN also contains relatively high amounts of copper (Cu) and zinc (Zn), but the importance of these metals in FRDA has not been established. This report describes nondestructive quantitative X-ray fluorescence (XRF) and "mapping" of Fe, Cu, and Zn in polyethylene glycol–dimethylsulfoxide (PEG/DMSO)-embedded DN of 10 FRDA patients and 13 controls. Fe fluorescence arose predominantly from the hilar white matter, whereas Cu and Zn were present at peak levels in DN gray matter. Despite collapse of the DN in FRDA, the location of the peak Fe signal did not change. In contrast, the Cu and Zn regions broadened and overlapped extensively with the Fe-rich region. Maximal metal concentrations did not differ from normal (in micrograms per milliliter of solid PEG/DMSO as means ± S.D.): Fe normal, 364 ± 117, FRDA, 344 ± 159; Cu normal, 33 ± 13, FRDA, 33 ± 18; and Zn normal, 32 ± 16, FRDA, 33 ± 19. Tissues were recovered from PEG/DMSO and transferred into paraffin for matching with immunohistochemistry of neuron-specific enolase (NSE), glutamic acid decarboxylase (GAD), and ferritin. NSE and GAD reaction products confirmed neuronal atrophy and grumose degeneration that coincided with abnormally diffuse Cu and Zn zones. Ferritin immunohistochemistry matched Fe XRF maps, revealing the most abundant reaction product in oligodendroglia of the DN hilus. In FRDA, these cells were smaller and more numerous than normal. In the atrophic DN gray matter of FRDA, anti-ferritin labeled mostly hypertrophic microglia. Immunohistochemistry and immunofluorescence of the Cu-responsive proteins Cu,Zn-superoxide dismutase and Cu++-transporting ATPase α-peptide did not detect specific responses to Cu redistribution in FRDA. In contrast, metallothionein (MT)-positive processes were more abundant than normal and contributed to the gliosis of the DN. The isoforms of MT, MT-1/2, and brain-specific MT-3 displayed only limited co-localization with glial fibrillary acidic protein. The results suggest that MT can provide effective protection against endogenous Cu and Zn toxicity in FRDA, similar to the neuroprotective sequestration of Fe in holoferritin.
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