Molecular Defects in Friedreich's Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities.
Molecular Defects in Friedreich's Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities.
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DOI：
10.3389/fmolb.2020.569293
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发表时间：
2020
影响因子：
5
通讯作者：
Kosman DJ
中科院分区：
文献类型：
--
作者：
Smith FM;Kosman DJ
Friedreich‘s共济失调(Friedreich’s ataxia，FRDA)是一种以进行性感觉-运动丧失、神经变性、脑铁蓄积为特征的多方面疾病，最终死于肥厚性心肌病。FRDA是在Frataxin(FXN)丢失之后发生的，FXN是一种线粒体伴侣蛋白，需要将铁结合到铁-硫簇和血红素前体中。自1996年发现FRDA的分子基础以来，二十多年的研究一直致力于在全身和分子水平上了解疾病的时间表现。早期研究表明，在人类和酵母模型中，细胞铁强烈失调，随后发生氧化应激。从那时起，与抗氧化防御和能量代谢衰竭相关的FRDA的病理生理机制已成为细胞内铁伴侣调节失调的核心。同时，对细胞骨架组织的变化给予了有限的考虑，这是第一批注意到的分子缺陷之一。这些变化包括肌动蛋白单体的翻译后氧化谷胱甘肽基化和细胞骨架调节因子PIP5K1β的差异DNA加工。目前对于FRDA尚不清楚，但在FXN缺乏的细胞生理学的背景下众所周知的是对细胞骨架的影响；这种肌动蛋白细丝的分解对屏障细胞所特有的细胞-细胞连接具有特别深刻的影响。对于像FRDA这样的神经退行性疾病，血脑屏障中脑微血管内皮细胞的这种细胞骨架和紧密连接的破坏可能是疾病病因的一个组成部分。这篇综述概述了这项研究的简要历史，并对FRDA中铁相关病理下游与肌动蛋白动力学相关的途径失调进行了深入的研究。本文的综述并不是要详尽无遗，而是敦促读者考虑细胞骨架的重要性，并理解氧化应激导致的FRDA相关细胞骨架功能障碍的有限知识。该综述对FRDA中神经退行性变伴脑铁蓄积(NBIA)的假说进行了审查，并结合特定的生化焦点进行了讨论。
Friedreich’s ataxia (FRDA) is a multi-faceted disease characterized by progressive sensory–motor loss, neurodegeneration, brain iron accumulation, and eventual death by hypertrophic cardiomyopathy. FRDA follows loss of frataxin (FXN), a mitochondrial chaperone protein required for incorporation of iron into iron–sulfur cluster and heme precursors. After the discovery of the molecular basis of FRDA in 1996, over two decades of research have been dedicated to understanding the temporal manifestations of disease both at the whole body and molecular level. Early research indicated strong cellular iron dysregulation in both human and yeast models followed by onset of oxidative stress. Since then, the pathophysiology due to dysregulation of intracellular iron chaperoning has become central in FRDA relative to antioxidant defense and run-down in energy metabolism. At the same time, limited consideration has been given to changes in cytoskeletal organization, which was one of the first molecular defects noted. These alterations include both post-translational oxidative glutathionylation of actin monomers and differential DNA processing of a cytoskeletal regulator PIP5K1β. Currently unknown in respect to FRDA but well understood in the context of FXN-deficient cell physiology is the resulting impact on the cytoskeleton; this disassembly of actin filaments has a particularly profound effect on cell–cell junctions characteristic of barrier cells. With respect to a neurodegenerative disorder such as FRDA, this cytoskeletal and tight junction breakdown in the brain microvascular endothelial cells of the blood–brain barrier is likely a component of disease etiology. This review serves to outline a brief history of this research and hones in on pathway dysregulation downstream of iron-related pathology in FRDA related to actin dynamics. The review presented here was not written with the intent of being exhaustive, but to instead urge the reader to consider the essentiality of the cytoskeleton and appreciate the limited knowledge on FRDA-related cytoskeletal dysfunction as a result of oxidative stress. The review examines previous hypotheses of neurodegeneration with brain iron accumulation (NBIA) in FRDA with a specific biochemical focus.
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影响因子：
4.1
作者：
CHAPPELL, JB
通讯作者：
CHAPPELL, JB
影响因子：
5.1
作者：
Bonilha da Silva, C.;Bergo, F. P. G.;Franca, M. C., Jr.
通讯作者：
Franca, M. C., Jr.
影响因子：
3.5
作者：
Carvalho, Andreia Neves;Marques, Carla;Gama, Maria Joao
通讯作者：
Gama, Maria Joao
影响因子：
3.4
作者：
Bienert, Gerd P.;Schjoerring, Jan K.;Jahn, Thomas P.
通讯作者：
Jahn, Thomas P.
影响因子：
5.3
作者：
Calkins, Marcus J.;Townsend, Jessica A.;Johnson, Delinda A.;Johnson, Jeffrey A.
通讯作者：
Johnson, Jeffrey A.