Barnett Institute of Chemical and Biological Analysis, Northeastern University, Boston, MA, 02115, USA.
Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts, 02115, United States.
Sci Rep. 2020 Feb 28;10(1):3715. doi: 10.1038/s41598-020-60431-6.
0.5-1% of ALS (Amyotrophic Lateral Sclerosis) and Parkinson's disease (PD) are associated with mutations in the angiogenin (ANG). These mutations are thought to cause disease through a loss of ANG function, but this hypothesis has not been evaluated statistically. In addition, the potential for ANG to promote disease has not been considered. With the goal of better defining the etiology of ANG-ALS, we assembled all clinical onset and disease duration data and determined if these were correlated with biochemical properties of ANG variants. Loss of ANG stability and ribonuclease activity were found to correlate with early ALS onset, confirming an aspect of the prevailing model of ANG-ALS. Conversely, loss of ANG stability and ribonuclease activity correlated with longer survival following diagnosis, which is inconsistent with the prevailing model. These results indicate that functional ANG appears to decrease the risk of developing ALS but exacerbate ALS once in progress. These findings are rationalized in terms of studies demonstrating that distinct mechanisms contribute to ALS onset and progression and propose that ANG replacement or stabilization would benefit pre-symptomatic ANG-ALS patients. However, this study challenges the prevailing hypothesis that augmenting ANG will benefit symptomatic ANG-ALS patients. Instead, our results suggest that silencing of ANG activity may be beneficial for symptomatic ALS patients. This study will serve as a call-to-arms for neurologists to consistently publish ALS and PD patient's clinical data-if all ANG-ALS patients' data were available our findings could be tested with considerable statistical power.
ANG（血管生成素）的突变与 0.5%-1%的 ALS（肌萎缩侧索硬化症）和帕金森病（PD）有关。这些突变被认为是通过 ANG 功能丧失导致疾病的，但这一假设尚未进行统计学评估。此外，ANG 促进疾病的潜力尚未被考虑。为了更好地确定 ANG-ALS 的病因，我们收集了所有的临床发病和疾病持续时间的数据，并确定这些数据是否与 ANG 变异体的生化特性相关。ANG 稳定性和核糖核酸酶活性的丧失与 ALS 的早期发病相关，这证实了 ANG-ALS 的流行模型的一个方面。相反，ANG 稳定性和核糖核酸酶活性的丧失与诊断后存活时间延长相关，这与流行模型不一致。这些结果表明，功能性 ANG 似乎降低了发展为 ALS 的风险，但一旦进展，就会加重 ALS。根据研究表明，不同的机制有助于 ALS 的发病和进展，这些发现可以用 ANG 替代或稳定会使 ANG-ALS 患者受益的观点来解释。然而，这项研究挑战了增强 ANG 将使有症状的 ANG-ALS 患者受益的流行假设。相反，我们的研究结果表明，沉默 ANG 的活性可能对有症状的 ALS 患者有益。这项研究将呼吁神经科医生始终如一地公布 ALS 和 PD 患者的临床数据——如果所有 ANG-ALS 患者的数据都可用，我们的发现可以用相当大的统计能力进行测试。
