Calcium Deregulation: Novel Insights to Understand Friedreich's Ataxia Pathophysiology.
Calcium Deregulation: Novel Insights to Understand Friedreich's Ataxia Pathophysiology.
复制标题
DOI：
10.3389/fncel.2018.00264
复制
发表时间：
2018
影响因子：
5.3
通讯作者：
Giunti P
中科院分区：
文献类型：
--
作者：
Abeti R;Brown AF;Maiolino M;Patel S;Giunti P
弗里德赖希共济失调（FRDA）是一种以背根神经节、小脑变性和心肌病为特征的神经退行性疾病。心力衰竭是FRDA患者最常见的死亡原因之一。fraataxin是一种小的线粒体蛋白，其缺乏导致FRDA的所有临床和形态学表现。我们的研究重点是探讨未探索的钙稳态小脑颗粒神经元（CGNs）和FRDA细胞模型的心肌细胞，以了解变性的发病机制。神经元和心肌细胞中的Ca 2+稳态不仅对细胞健康至关重要，更重要的是在神经元和心肌细胞中产生动作电位。通过挑战CGN以及FRDA模型的成人和新生儿心肌细胞中的Ca 2+稳态，我们评估了共济失调蛋白减少对神经元和心脏生理病理学的影响。有趣的是，我们发现Ca 2+稳态改变了两种细胞类型。CGN在去极化条件下显示Ca 2+处理不当，这也反映在内质网（ER）含量中。在心肌细胞中，我们发现，肌浆网（SR）钙含量病理性减少，线粒体钙摄取受损。这种现象是由于在FRDA样条件下过度的氧化应激以及随后在SR/ER和线粒体水平上的关键参与者的异常调节，其通常恢复Ca 2+稳态。我们的研究结果表明，在神经元和心肌细胞中，储存内Ca 2+水平的降低对它们的生理学具有相当的不利影响。在心肌细胞中，我们发现ryanodine受体（RyRs）可能泄漏并从SR中排出更多的Ca 2+。同时线粒体摄取发生改变，我们发现维生素E可以恢复这种缺陷。此外，维生素E可防止缺氧再灌注损伤诱导的细胞死亡，揭示了维生素E作为FRDA心肌病潜在治疗工具的新特性。
Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. Heart failure is one of the most common causes of death for FRDA patients. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. The focus of our study was to investigate the unexplored Ca2+ homeostasis in cerebellar granule neurons (CGNs) and in cardiomyocytes of FRDA cellular models to understand the pathogenesis of degeneration. Ca2+ homeostasis in neurons and cardiomyocytes is not only crucial for the cellular wellbeing but more importantly to generate action potential in both neurons and cardiomyocytes. By challenging Ca2+ homeostasis in CGNs, and in adult and neonatal cardiomyocytes of FRDA models, we have assessed the impact of frataxin decrease on both neuronal and cardiac physiopathology. Interestingly, we have found that Ca2+ homeostasis is altered both cell types. CGNs showed a Ca2+ mishandling under depolarizing conditions and this was also reflected in the endoplasmic reticulum (ER) content. In cardiomyocytes we found that the sarcoplasmic reticulum (SR) Ca2+ content was pathologically reduced, and that mitochondrial Ca2+ uptake was impaired. This phenomenon is due to the excess of oxidative stress under FRDA like conditions and the consequent aberrant modulation of key players at the SR/ER and mitochondrial level that usually restore the Ca2+ homeostasis. Our findings demonstrate that in both neurons and cardiomyocytes the decreased Ca2+ level within the stores has a comparable detrimental impact in their physiology. In cardiomyocytes, we found that ryanodine receptors (RyRs) may be leaking and expel more Ca2+ out from the SR. At the same time mitochondrial uptake was altered and we found that Vitamin E can restore this defect. Moreover, Vitamin E protects from cell death induced by hypoxia-reperfusion injury, revealing novel properties of Vitamin E as potential therapeutic tool for FRDA cardiomyopathy.
登录
查看更多内容
影响因子：
16
作者：
Dong Z;Shanmughapriya S;Tomar D;Siddiqui N;Lynch S;Nemani N;Breves SL;Zhang X;Tripathi A;Palaniappan P;Riitano MF;Worth AM;Seelam A;Carvalho E;Subbiah R;Jaña F;Soboloff J;Peng Y;Cheung JY;Joseph SK;Caplan J;Rajan S;Stathopulos PB;Madesh M
通讯作者：
Madesh M
影响因子：
30.8
作者：
Puccio, H;Simon, D;Koenig, M
通讯作者：
Koenig, M
影响因子：
--
作者：
Hart, PE;Lodi, R;Cooper, JM
通讯作者：
Cooper, JM
影响因子：
4
作者：
Díaz, ME;Graham, HK;Eisner, DA
通讯作者：
Eisner, DA
影响因子：
64.5
作者：
Marx, SO;Reiken, S;Marks, AR
通讯作者：
Marks, AR