Koeppen Arnulf H, Michael Susan C, Knutson Mitchell D, Haile David J, Qian Jiang, Levi Sonia, Santambrogio Paolo, Garrick Michael D, Lamarche Jacques B
Research, Veterans Affairs Medical Center, Albany, NY 12208, USA.
Acta Neuropathol. 2007 Aug;114(2):163-73. doi: 10.1007/s00401-007-0220-y. Epub 2007 Apr 11.
Frataxin deficiency in Friedreich's ataxia (FRDA) causes cardiac, endocrine, and nervous system manifestations. Frataxin is a mitochondrial protein, and adequate amounts are essential for cellular iron homeostasis. The main histological lesion in the brain of FRDA patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed grumose degeneration. This cerebellar nucleus may be especially susceptible to FRDA because it contains abundant iron. We examined total iron and selected iron-responsive proteins in the dentate nucleus of nine patients with FRDA and nine normal controls by biochemical and microscopic techniques. Total iron (1.53 +/- 0.53 mumol/g wet weight) and ferritin (206.9 +/- 46.6 mug/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 +/- 0.88 mumol/g; ferritin: 210.9 +/- 9.0 mug/g) but Western blots exhibited a shift to light ferritin subunits. Immunocytochemistry of the dentate nucleus revealed loss of juxtaneuronal ferritin-containing oligodendroglia and prominent ferritin immunoreactivity in microglia and astrocytes. Mitochondrial ferritin was not detectable by immunocytochemistry. Stains for the divalent metal transporter 1 confirmed neuronal loss while endothelial cells reacting with antibodies to transferrin receptor 1 protein showed crowding of blood vessels due to collapse of the normal neuropil. Regions of grumose degeneration were strongly reactive for ferroportin. Purkinje cell bodies, their dendrites and axons, were also ferroportin-positive, and it is likely that grumose degeneration is the morphological manifestation of mitochondrial iron dysmetabolism in the terminals of corticonuclear fibers. Neuronal loss in the dentate nucleus is the likely result of trans-synaptic degeneration.
弗里德赖希共济失调（FRDA）中的铁调素缺乏会导致心脏、内分泌和神经系统表现。铁调素是一种线粒体蛋白，足够的量对于细胞铁稳态至关重要。FRDA患者大脑中的主要组织学病变是神经元萎缩以及齿状核中突触终末的一种特殊增殖，称为颗粒样变性。这个小脑核可能对FRDA特别敏感，因为它含有丰富的铁。我们通过生化和显微镜技术检查了9例FRDA患者和9例正常对照的齿状核中的总铁和选定的铁反应蛋白。FRDA中的总铁（1.53±0.53μmol/g湿重）和铁蛋白（206.9±46.6μg/g湿重）与正常对照（铁：1.78±0.88μmol/g；铁蛋白：210.9±9.0μg/g）无显著差异，但蛋白质免疫印迹显示向轻链铁蛋白亚基转变。齿状核的免疫细胞化学显示神经元周围含铁血黄素的少突胶质细胞丢失，小胶质细胞和星形胶质细胞中有明显的铁蛋白免疫反应性。通过免疫细胞化学未检测到线粒体铁蛋白。二价金属转运蛋白1的染色证实了神经元丢失，而与转铁蛋白受体1蛋白抗体反应的内皮细胞显示由于正常神经纤维网塌陷导致血管拥挤。颗粒样变性区域对铁转运蛋白有强烈反应。浦肯野细胞体、其树突和轴突也呈铁转运蛋白阳性，颗粒样变性很可能是皮质核纤维终末线粒体铁代谢异常的形态学表现。齿状核中的神经元丢失可能是跨突触变性的结果。
