Research Services, Veterans Affairs Medical Center, 113 Holland Ave, Albany, NY 12208, USA.
Acta Neuropathol Commun. 2013 Jun 19;1:26. doi: 10.1186/2051-5960-1-26.
Friedreich ataxia (FA) causes distinctive lesions of dorsal root ganglia (DRG), including neuronal atrophy, satellite cell hyperplasia, and absorption of dying nerve cells into residual nodules. Two mechanisms may be involved: hypoplasia of DRG neurons from birth and superimposed iron (Fe)- and zinc (Zn)-mediated oxidative injury. This report presents a systematic analysis of DRG in 7 FA patients and 13 normal controls by X-ray fluorescence (XRF) of polyethylene glycol-embedded DRG; double-label confocal immunofluorescence microscopy of Zn- and Fe-related proteins; and immunohistochemistry of frataxin and the mitochondrial marker, ATP synthase F1 complex V β-polypeptide (ATP5B).
XRF revealed normal total Zn- and Fe-levels in the neural tissue of DRG in FA (mean ± standard deviation): Zn=5.46±2.29 μg/ml, Fe=19.99±13.26 μg/ml in FA; Zn=8.16±6.19 μg/ml, Fe=23.85±12.23 μg/ml in controls. Despite these unchanged total metal concentrations, Zn- and Fe-related proteins displayed major shifts in their cellular localization. The Zn transporter Zip14 that is normally expressed in DRG neurons and satellite cells became more prominent in hyperplastic satellite cells and residual nodules. Metallothionein 3 (MT3) stains confirmed reduction of neuronal size in FA, but MT3 expression remained low in hyperplastic satellite cells. In contrast, MT1/2 immunofluorescence was prominent in proliferating satellite cells. Neuronal ferritin immunofluorescence declined but remained strong in hyperplastic satellite cells and residual nodules. Satellite cells in FA showed a larger number of mitochondria expressing ATB5B. Frataxin immunohistochemistry in FA confirmed small neuronal sizes, irregular distribution of reaction product beneath the plasma membrane, and enhanced expression in hyperplastic satellite cells.
The pool of total cellular Zn in normal DRG equals 124.8 μM, which is much higher than needed for the proper function of Zn ion-dependent proteins. It is likely that any disturbance of Zn buffering by Zip14 and MT3 causes mitochondrial damage and cell death. In contrast to Zn, sequestration of Fe in hyperplastic satellite cells may represent a protective mechanism. The changes in the cellular localization of Zn- and Fe-handling proteins suggest metal transfer from degenerating DRG neurons to activated satellite cells and connect neuronal metal dysmetabolism with the pathogenesis of the DRG lesion in FA.
弗里德赖希共济失调（FA）会导致背根神经节（DRG）出现独特的病变，包括神经元萎缩、卫星细胞增生以及死亡神经细胞被吸收到残余结节中。可能涉及两种机制：出生时 DRG 神经元的发育不良和叠加的铁（Fe）和锌（Zn）介导的氧化损伤。本报告通过对聚乙二醇包埋的 DRG 进行 X 射线荧光（XRF）、Zn 和 Fe 相关蛋白的双标记共聚焦免疫荧光显微镜检查以及 frataxin 和线粒体标记物 ATP 合酶 F1 复合物 V β-多肤（ATP5B）的免疫组织化学，对 7 例 FA 患者和 13 例正常对照者的 DRG 进行了系统分析。
XRF 显示 FA 患者 DRG 神经组织中的总 Zn 和 Fe 水平正常（平均值±标准差）：Zn=5.46±2.29μg/ml，Fe=19.99±13.26μg/ml；Zn=8.16±6.19μg/ml，Fe=23.85±12.23μg/ml。尽管这些总金属浓度没有变化，但 Zn 和 Fe 相关蛋白的细胞定位发生了重大变化。正常情况下在 DRG 神经元和卫星细胞中表达的 Zn 转运蛋白 Zip14 在增生的卫星细胞和残余结节中变得更加突出。金属硫蛋白 3（MT3）染色证实 FA 中神经元体积减小，但增生的卫星细胞中 MT3 表达仍然较低。相比之下，MT1/2 免疫荧光在增殖的卫星细胞中较为明显。神经元铁蛋白免疫荧光减弱，但在增生的卫星细胞和残余结节中仍较强。FA 中的卫星细胞表达更多表达 ATP5B 的线粒体。FA 中的 frataxin 免疫组织化学证实神经元体积较小，细胞质膜下反应产物分布不规则，增生的卫星细胞表达增强。
正常 DRG 中的总细胞 Zn 池为 124.8μM，远高于 Zn 离子依赖蛋白正常功能所需的水平。Zip14 和 MT3 对 Zn 缓冲的任何干扰都可能导致线粒体损伤和细胞死亡。与 Zn 不同，增生的卫星细胞中 Fe 的隔离可能代表一种保护机制。Zn 和 Fe 处理蛋白细胞定位的变化表明，金属从退化的 DRG 神经元转移到激活的卫星细胞，并将神经元金属代谢紊乱与 FA 中 DRG 病变的发病机制联系起来。
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