The era of cryptic exons: implications for ALS-FTD.
The era of cryptic exons: implications for ALS-FTD.
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DOI：
10.1186/s13024-023-00608-5
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发表时间：
2023-03-15
影响因子：
15.1
通讯作者：
中科院分区：
文献类型：
--
作者：
TDP-43 是一种 RNA 结合蛋白，在剪接中发挥着至关重要的核作用，并且在一系列神经退行性疾病中从细胞核错误定位到细胞质。 TDP-43蛋白病涵盖一系列无法治愈、异质且日益流行的神经退行性疾病，包括肌萎缩侧索硬化症和额颞叶痴呆疾病谱以及阿尔茨海默病的很大一部分。目前还没有针对 TDP-43 蛋白病的定向疾病缓解疗法，也无法区分谁在死亡前受到影响。现在已经清楚，TDP-43 蛋白病会导致许多分子变化，包括神秘外显子的去抑制和包含。重要的是，其中一些神秘外显子会导致关键神经元蛋白的丢失，并已被证明是疾病发病机制中的关键致病因素（例如 STMN2），并且能够改变疾病进展（例如 UNC13A）。因此，这些异常剪接事件成为恢复功能基因表达的有希望的新治疗靶点。此外，这些神秘外显子的存在对于受 TDP-43 蛋白病影响的患者和大脑区域具有高度特异性，这为开发用于早期检测和患者分层的生物标志物提供了潜力。总之，神秘外显子的发现为 TDP-43 蛋白病的新型诊断和治疗带来了希望。
TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer’s disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g., STMN2), as well as being able to modify disease progression (e.g., UNC13A). Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies.
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影响因子：
3.5
作者：
Eser, Gokce;Topaloglu, Haluk
通讯作者：
Topaloglu, Haluk
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
DOI：
10.1136/jnnp-2020-322983
发表时间：
2020-11-11
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
de Boer EMJ;Orie VK;Williams T;Baker MR;De Oliveira HM;Polvikoski T;Silsby M;Menon P;van den Bos M;Halliday GM;van den Berg LH;Van Den Bosch L;van Damme P;Kiernan MC;van Es MA;Vucic S
通讯作者：
Vucic S
影响因子：
4.2
作者：
Chiò A;Mora G;Restagno G;Brunetti M;Ossola I;Barberis M;Ferrucci L;Canosa A;Manera U;Moglia C;Fuda G;Traynor BJ;Calvo A
通讯作者：
Calvo A
影响因子：
12.7
作者：
Gao, Fei;Hu, Mei;Zhang, Jian;Hashem, Jack;Chen, Chu
通讯作者：
Chen, Chu