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Neuropathological and biochemical investigation of Hereditary Ferritinopathycases with ferritin light chain mutation: Prominent protein aggregation in the absence of major mitochondrial or oxidative stress
Neuropathology and Applied Neurobiology ( IF 5 ) Pub Date : 2020-06-19 , DOI: 10.1111/nan.12634 M Kurzawa-Akanbi 1, 2 , M Keogh 1, 3, 4 , E Tsefou 2 , L Ramsay 5, 6 , M Johnson 5 , S Keers 5 , L Wsa Ochieng 2 , A McNair 2 , P Singh 2 , A Khan 3 , A Pyle 1 , G Hudson 1 , P G Ince 6 , J Attems 7 , J Burn 1, 8 , P F Chinnery 1, 4 , C M Morris 2, 5
Neuropathology and Applied Neurobiology ( IF 5 ) Pub Date : 2020-06-19 , DOI: 10.1111/nan.12634 M Kurzawa-Akanbi 1, 2 , M Keogh 1, 3, 4 , E Tsefou 2 , L Ramsay 5, 6 , M Johnson 5 , S Keers 5 , L Wsa Ochieng 2 , A McNair 2 , P Singh 2 , A Khan 3 , A Pyle 1 , G Hudson 1 , P G Ince 6 , J Attems 7 , J Burn 1, 8 , P F Chinnery 1, 4 , C M Morris 2, 5
Affiliation
AIMS
Neuroferritinopathyor Hereditary Ferritinopathy (HF)is an autosomal dominant movement disorder due to mutation in the light chain of the iron storage protein ferritin (FTL).HF is the only late-onset neurodegeneration with brain iron accumulation disorder andstudy of HF offers a unique opportunity to understand the role of iron in more common neurodegenerative syndromes. METHODS
We carried out pathological and biochemical studies of six individuals with the same pathogenic FTL mutation. RESULTS
CNS pathological changes were most prominent in the basal ganglia and cerebellar dentate, echoing the normal pattern of brain iron accumulation.Accumulation of ferritin and iron was conspicuous in cells with a phenotype suggestingoligodendrocytes, withaccompanying neuronal pathology and neuronal loss. Neuronsstill survived however, despite extensive adjacent glial iron deposition, suggesting neuronal loss is a downstream event.Typical age-related neurodegenerative pathology was not normally present.Uniquely, the extensive aggregates of ubiquitinated ferritin identified indicate that abnormal FTLcan aggregate, reflecting theintrinsicability of FTL to self-assemble.Ferritin aggregates were seenin neuronal and glial nuclei showing parallels with Huntington's disease. There was no evidence of oxidative stress activation nor any significant mitochondrial pathologyin the affected basal ganglia. CONCLUSIONS
HF shows hallmarks of a protein aggregation disorder, in addition to iron accumulation.Degeneration in HF is not accompanied by age-related neurodegenerative pathology and the lack of evidence of oxidative stress and mitochondrial damage suggests these are not key mediators of neurodegeneration in HF, casting light on other neurodegenerative diseases characterised by iron deposition.
中文翻译:
具有铁蛋白轻链突变的遗传性铁蛋白病病例的神经病理学和生化研究:在没有主要线粒体或氧化应激的情况下突出的蛋白质聚集
AIMS 神经铁蛋白病或遗传性铁蛋白病 (HF) 是一种常染色体显性遗传运动障碍,原因是铁储存蛋白铁蛋白 (FTL) 的轻链发生突变。HF 是唯一伴有脑铁积累障碍的迟发性神经变性,对 HF 的研究提供了独特的机会了解铁在更常见的神经退行性综合征中的作用。方法 我们对 6 名具有相同致病性 FTL 突变的个体进行了病理学和生化研究。结果中枢神经系统病理改变以基底节和小脑齿状最为突出,与脑铁蓄积的正常模式相呼应。铁蛋白和铁的蓄积在细胞中明显,表型提示少突胶质细胞,并伴有神经元病理和神经元丢失。然而,神经元仍然幸存下来,尽管广泛的邻近神经胶质铁沉积,表明神经元丢失是下游事件。典型的与年龄相关的神经退行性病变通常不存在。独特地,泛素化铁蛋白的广泛聚集表明异常 FTL 可以聚集,反映 FTL 自组装的内在性。在神经元和神经胶质细胞核中观察到铁蛋白聚集体,与亨廷顿病相似。在受影响的基底节中没有氧化应激激活的证据,也没有任何显着的线粒体病理学。结论 除铁积累外,HF 还显示出蛋白质聚集障碍的特征。
更新日期:2020-06-19
中文翻译:
具有铁蛋白轻链突变的遗传性铁蛋白病病例的神经病理学和生化研究:在没有主要线粒体或氧化应激的情况下突出的蛋白质聚集
AIMS 神经铁蛋白病或遗传性铁蛋白病 (HF) 是一种常染色体显性遗传运动障碍,原因是铁储存蛋白铁蛋白 (FTL) 的轻链发生突变。HF 是唯一伴有脑铁积累障碍的迟发性神经变性,对 HF 的研究提供了独特的机会了解铁在更常见的神经退行性综合征中的作用。方法 我们对 6 名具有相同致病性 FTL 突变的个体进行了病理学和生化研究。结果中枢神经系统病理改变以基底节和小脑齿状最为突出,与脑铁蓄积的正常模式相呼应。铁蛋白和铁的蓄积在细胞中明显,表型提示少突胶质细胞,并伴有神经元病理和神经元丢失。然而,神经元仍然幸存下来,尽管广泛的邻近神经胶质铁沉积,表明神经元丢失是下游事件。典型的与年龄相关的神经退行性病变通常不存在。独特地,泛素化铁蛋白的广泛聚集表明异常 FTL 可以聚集,反映 FTL 自组装的内在性。在神经元和神经胶质细胞核中观察到铁蛋白聚集体,与亨廷顿病相似。在受影响的基底节中没有氧化应激激活的证据,也没有任何显着的线粒体病理学。结论 除铁积累外,HF 还显示出蛋白质聚集障碍的特征。