Arnulf H Koeppen, Rahman F Rafique, Joseph E Mazurkiewicz, Steven Pelech, Catherine Sutter, Qishan Lin, Jiang Qian
{"title":"Friedreich cardiomyopathy is a desminopathy.","authors":"Arnulf H Koeppen, Rahman F Rafique, Joseph E Mazurkiewicz, Steven Pelech, Catherine Sutter, Qishan Lin, Jiang Qian","doi":"10.17879/freeneuropathology-2021-3679","DOIUrl":null,"url":null,"abstract":"<p><p>Heart disease is an integral part of Friedreich ataxia (FA) and the most common cause of death in this autosomal recessive disease. The result of the mutation is lack of frataxin, a small mitochondrial protein. The clinical and pathological phenotypes of FA are complex, involving brain, spinal cord, dorsal root ganglia, sensory nerves, heart, and endocrine pancreas. The hypothesis is that frataxin deficiency causes downstream changes in the proteome of the affected tissues, including the heart. A proteomic analysis of heart proteins in FA cardiomyopathy by antibody microarray, Western blots, immunohistochemistry, and double-label laser scanning confocal immunofluorescence microscopy revealed upregulation of desmin and its chaperone protein, αB-crystallin. In normal hearts, these two proteins are co-localized at intercalated discs and Z discs. In FA, desmin and αB-crystallin aggregate, causing chaotic modification of intercalated discs, clustering of mitochondria, and destruction of the contractile apparatus of cardiomyocytes. Western blots of tissue lysates in FA cardiomyopathy reveal a truncated desmin isoprotein that migrates at a lower molecular weight range than wild type desmin. While desmin and αB-crystallin are not mutated in FA, the accumulation of these proteins in FA hearts allows the conclusion that FA cardiomyopathy is a desminopathy akin to desmin myopathy of skeletal muscle.</p>","PeriodicalId":73056,"journal":{"name":"Free neuropathology","volume":"2 ","pages":"34"},"PeriodicalIF":0.0000,"publicationDate":"2021-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10209862/pdf/freeneuropathol-02-34-3679.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free neuropathology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.17879/freeneuropathology-2021-3679","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2021/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
Heart disease is an integral part of Friedreich ataxia (FA) and the most common cause of death in this autosomal recessive disease. The result of the mutation is lack of frataxin, a small mitochondrial protein. The clinical and pathological phenotypes of FA are complex, involving brain, spinal cord, dorsal root ganglia, sensory nerves, heart, and endocrine pancreas. The hypothesis is that frataxin deficiency causes downstream changes in the proteome of the affected tissues, including the heart. A proteomic analysis of heart proteins in FA cardiomyopathy by antibody microarray, Western blots, immunohistochemistry, and double-label laser scanning confocal immunofluorescence microscopy revealed upregulation of desmin and its chaperone protein, αB-crystallin. In normal hearts, these two proteins are co-localized at intercalated discs and Z discs. In FA, desmin and αB-crystallin aggregate, causing chaotic modification of intercalated discs, clustering of mitochondria, and destruction of the contractile apparatus of cardiomyocytes. Western blots of tissue lysates in FA cardiomyopathy reveal a truncated desmin isoprotein that migrates at a lower molecular weight range than wild type desmin. While desmin and αB-crystallin are not mutated in FA, the accumulation of these proteins in FA hearts allows the conclusion that FA cardiomyopathy is a desminopathy akin to desmin myopathy of skeletal muscle.
心脏病是弗里德赖希共济失调(FA)的一个组成部分,也是这种常染色体隐性疾病中最常见的死亡原因。突变的结果是缺乏一种小的线粒体蛋白——卵黄蛋白。FA的临床和病理表型复杂,累及脑、脊髓、背根神经节、感觉神经、心脏和内分泌胰腺。假设是,卵黄蛋白缺乏会导致受影响组织(包括心脏)蛋白质组的下游变化。通过抗体芯片、Western blots、免疫组织化学和双标记激光扫描共聚焦免疫荧光显微镜对FA型心肌病患者心脏蛋白进行蛋白质组学分析,发现desmin及其伴侣蛋白α b -晶体蛋白上调。在正常心脏中,这两种蛋白共定位于嵌入盘和Z盘。在FA中,聚乳酸蛋白和α b -晶体蛋白聚集,导致嵌入盘的混乱修饰,线粒体聚集,心肌细胞收缩器破坏。FA型心肌病组织裂解物的Western blots显示一个截短的异蛋白,其迁移的分子量范围低于野生型异蛋白。虽然精蛋白和α b -结晶蛋白在FA中没有突变,但这些蛋白在FA心脏中的积累可以得出结论,FA心肌病是一种类似于骨骼肌精蛋白肌病的精蛋白病。