Sorcin is an early marker of neurodegeneration, Ca(2+) dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases.
Sorcin is an early marker of neurodegeneration, Ca(2+) dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases.
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DOI：
10.1038/s41419-020-03063-y
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发表时间：
2020-10-15
影响因子：
9
通讯作者：
Colotti G
中科院分区：
文献类型：
--
作者：
Genovese I;Giamogante F;Barazzuol L;Battista T;Fiorillo A;Vicario M;D'Alessandro G;Cipriani R;Limatola C;Rossi D;Sorrentino V;Poser E;Mosca L;Squitieri F;Perluigi M;Arena A;van Petegem F;Tito C;Fazi F;Giorgi C;Calì T;Ilari A;Colotti G
钙信号传导失调正在成为阿尔茨海默病 (AD)、帕金森病 (PD) 和亨廷顿病 (HD) 等神经退行性疾病发病机制中的一个关键特征，针对这一过程可能具有治疗益处。从这个角度来看，研究调节细胞内钙稳态的蛋白质非常重要。 Sorcin 是人脑中表达最多的钙结合蛋白之一；它的过度表达会增加心脏和其他细胞类型中的内质网 (ER) 钙浓度并降低 ER 应激。据推测，Sorcin 与神经退行性疾病有关，因为它可以抵消与神经退行性疾病相关的胞质钙水平升高。在目前的工作中，我们发现与正常细胞相比，Sorcin 表达水平在 AD、PD 和 HD 的细胞、动物和人类模型中显着增加。 Sorcin 与神经元和小胶质细胞中的 RyR 部分共定位；分别含有大量 RyR2 和 RyR3 的微粒体的功能实验表明，Sorcin 能够调节这些 ER 钙通道。 SPR 证明了 Sorcin 与 RyR2 和 RyR3 相互作用的分子基础。 Sorcin 还以钙依赖性方式与 SERCA2 和 Sigma-1 受体等其他 ER 蛋白相互作用。我们还表明，Sorcin 调节 ER 钙瞬变：Sorcin 增加 ER 钙摄取速度（增加 SERCA 活性）。这里提供的数据表明，Sorcin 可能代表神经退行性疾病的新型早期标志物和对依赖于神经退行性变的细胞应激的反应。
Dysregulation of calcium signaling is emerging as a key feature in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), and targeting this process may be therapeutically beneficial. Under this perspective, it is important to study proteins that regulate calcium homeostasis in the cell. Sorcin is one of the most expressed calcium-binding proteins in the human brain; its overexpression increases endoplasmic reticulum (ER) calcium concentration and decreases ER stress in the heart and in other cellular types. Sorcin has been hypothesized to be involved in neurodegenerative diseases, since it may counteract the increased cytosolic calcium levels associated with neurodegeneration. In the present work, we show that Sorcin expression levels are strongly increased in cellular, animal, and human models of AD, PD, and HD, vs. normal cells. Sorcin partially colocalizes with RyRs in neurons and microglia cells; functional experiments with microsomes containing high amounts of RyR2 and RyR3, respectively, show that Sorcin is able to regulate these ER calcium channels. The molecular basis of the interaction of Sorcin with RyR2 and RyR3 is demonstrated by SPR. Sorcin also interacts with other ER proteins as SERCA2 and Sigma-1 receptor in a calcium-dependent fashion. We also show that Sorcin regulates ER calcium transients: Sorcin increases the velocity of ER calcium uptake (increasing SERCA activity). The data presented here demonstrate that Sorcin may represent both a novel early marker of neurodegenerative diseases and a response to cellular stress dependent on neurodegeneration.
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影响因子：
5.3
作者：
Cipriani, Raffaela;Villa, Pia;Limatola, Cristina
通讯作者：
Limatola, Cristina
影响因子：
4.6
作者：
Ilari A;Fiorillo A;Poser E;Lalioti VS;Sundell GN;Ivarsson Y;Genovese I;Colotti G
通讯作者：
Colotti G
影响因子：
3.3
作者：
Gracy, KN;Clarke, CL;Pickel, VM
通讯作者：
Pickel, VM
影响因子：
2.9
作者：
Colotti, Gianni;Zamparelli, Carlotta;Chiancone, Emilia
通讯作者：
Chiancone, Emilia
影响因子：
9
作者：
Genovese I;Fiorillo A;Ilari A;Masciarelli S;Fazi F;Colotti G
通讯作者：
Colotti G