Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized with progressive muscle atrophy. We have attempted to establish the link between angiogenesis and cellular survival in the pathogenesis of ALS by compiling evidence described in various scientific reports. The phenotypes of human ALS have earlier been captured in the mutant SOD1 mice as well as by targeted deletion of the hypoxia response element (HRE) from the promoter of the mouse gene for vascular endothelial growth factor (VEGF). Indirect evidence shows that angiogenesis can help prevent oxidative stress, and hence, enhance cell survival. VEGF and angiogenin chiefly regulate the process of angiogenesis. Transactive response DNA-binding protein 43 (TDP-43) is usually found inside the nucleus, but in large number of cases of ALS, it accumulates in the cytoplasm (TDP-43 proteinopathy). Interestingly, TDP-43 proteinopathy is found to be aggravated in the presence of the OPTN mutation, which is the genetic factor that is responsible for such accumulation. Interaction of TDP-43 with progranulin can further affect the angiogenesis in ALS patients by regulating activity of VEGF receptors, but conclusive evidence is needed to establish its role in pathogenesis of ALS. Certain mutations in UBQLN2 and UBQLN4 indicate that ubiquitination has a role in ALS pathobiology, but its link to angiogenesis has not been adequately studied. Recent studies have shown that several mutations in RNA-binding proteins (RBPs) can also cause ALS. Conclusively, in this review, we have attempted to argue the role of angiogenesis in enhanced ALS survival rate is probably regulated with the activation of NF-κβ. Additionally, interaction between OPTN and TDP-43 can also impact the transcription of various angiogenic molecules. Whether targeting angiogenic substances or TDP-43 can provide clues about extending ALS survival rate, in combination with current treatments, can only be evaluated after additional studies.

中文翻译：

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肌萎缩侧索硬化生存中以血管生成为中心的分子串扰：机制见解。

肌萎缩侧索硬化（ALS）是一种神经退行性疾病，其特征是进行性肌肉萎缩。我们试图通过汇编各种科学报告中描述的证据，在 ALS 的发病机制中建立血管生成和细胞存活之间的联系。人类 ALS 的表型早先在突变型 SOD1 小鼠中以及通过从小鼠血管内皮生长因子 (VEGF) 基因的启动子中靶向删除缺氧反应元件 (HRE) 来捕获。间接证据表明，血管生成有助于防止氧化应激，从而提高细胞存活率。VEGF和血管生成素主要调节血管生成过程。反式反应 DNA 结合蛋白 43 (TDP-43) 通常存在于细胞核内，但在大量 ALS 病例中，它在细胞质中积累（TDP-43 蛋白病）。有趣的是，发现 TDP-43 蛋白病在 OPTN 突变存在的情况下会加重，OPTN 突变是导致这种积累的遗传因素。TDP-43 与颗粒蛋白前体的相互作用可通过调节 VEGF 受体的活性进一步影响 ALS 患者的血管生成，但需要确凿的证据来确定其在 ALS 发病机制中的作用。UBQLN2 和 UBQLN4 中的某些突变表明泛素化在 ALS 病理生物学中起作用，但尚未充分研究其与血管生成的联系。最近的研究表明，RNA 结合蛋白 (RBP) 的几种突变也会导致 ALS。最后，在这次审查中，我们试图论证血管生成在增强 ALS 存活率中的作用可能与 NF-κβ 的激活有关。此外，OPTN 和 TDP-43 之间的相互作用也会影响各种血管生成分子的转录。是否靶向血管生成物质或 TDP-43 可以提供有关延长 ALS 存活率的线索，结合目前的治疗，只能在额外的研究后进行评估。