C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress.
C9orf72 poly(PR) mediated neurodegeneration is associated with nucleolar stress.
复制标题
C9orf72 Poly(PR) 介导的神经变性与核仁应激相关。
DOI：
10.1101/2023.02.16.528809
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Trotti,D
中科院分区：
文献类型：
--
作者：
Cicardi,ME;Hallgren,JH;Mawrie,D;Krishnamurthy,K;Markandaiah,SS;Nelson,AT;Kankate,V;Anderson,EN;Pasinelli,P;Pandey,UB;Eischen,CM;Trotti,D
C9 orf 72基因中与ALS/FTD相关的内含子六核苷酸重复扩展以有义和反义方向异常翻译为二肽重复蛋白，其中聚脯氨酸-精氨酸（PR）在体外和体内显示出最具攻击性的神经毒性。当PR在神经元和其他细胞类型中异源表达时，PR分配到细胞核。我们表明，通过减少PR的核积累，我们可以大大降低其神经毒性。PR在核仁中强烈积累，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引起核仁压力和转录因子p53水平的增加。下调p53水平也防止PR介导的神经毒性在体外和体内模型。我们研究了PR是否可以诱导神经元的衰老表型。然而，我们没有观察到任何这种影响的迹象。相反，我们发现了通过caspase-3激活诱导程序性细胞死亡的证据。
The ALS/FTD-linked intronic hexanucleotide repeat expansion in theC9orf72gene is aberrantly translated in the sense and antisense directions into dipeptide repeat proteins, among which poly proline-arginine (PR) displays the most aggressive neurotoxicityin-vitroandin-vivo. 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 inin-vitroandin-vivomodels. 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.