Cicardi M E, Hallgren J H, Mawrie D, Krishnamurthy K, Markandaiah S S, Nelson A T, Kankate V, Anderson E N, Pasinelli P, Pandey U B, Eischen C M, Trotti D
Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.
Center for Neuroscience, Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
iScience. 2023 Jul 28;26(9):107505. doi: 10.1016/j.isci.2023.107505. eCollection 2023 Sep 15.
The ALS/FTD-linked intronic hexanucleotide repeat expansion in the gene is aberrantly translated in the sense and antisense directions into dipeptide repeat proteins, among which poly proline-arginine (PR) displays the most aggressive neurotoxicity and . PR partitions to the nucleus when heterologously expressed in neurons and other cell types. We show that by lessening the nuclear accumulation of PR, we can drastically reduce its neurotoxicity. PR strongly accumulates in the nucleolus, a nuclear structure critical in regulating the cell stress response. We determined that, in neurons, PR caused nucleolar stress and increased levels of the transcription factor p53. Downregulating p53 levels also prevented PR-mediated neurotoxicity both in and models. We investigated if PR could induce the senescence phenotype in neurons. However, we did not observe any indications of such an effect. Instead, we found evidence for the induction of programmed cell death via caspase-3 activation.
与肌萎缩侧索硬化症/额颞叶痴呆相关的基因内含子六核苷酸重复序列扩增在有义链和反义链方向上异常翻译为二肽重复蛋白，其中聚脯氨酸 - 精氨酸（PR）表现出最强的神经毒性。当在神经元和其他细胞类型中异源表达时，PR会定位于细胞核。我们发现，通过减少PR在细胞核中的积累，可以大幅降低其神经毒性。PR强烈积聚在核仁中，核仁是调节细胞应激反应的关键核结构。我们确定，在神经元中，PR会引起核仁应激并增加转录因子p53的水平。下调p53水平也能在体外和体内模型中预防PR介导的神经毒性。我们研究了PR是否能诱导神经元衰老表型。然而，我们没有观察到任何这种效应的迹象。相反，我们发现了通过半胱天冬酶 - 3激活诱导程序性细胞死亡的证据。
