C9ORF72 poly-PR disrupts expression of ALS/FTD-implicated STMN2 through SRSF7.

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Karen S Wang, Julie Smeyers, Kevin Eggan, Bogdan Budnik, Daniel A Mordes
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Abstract

A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and combined ALS/FTD. The repeat is transcribed in the sense and the antisense directions to produce several dipeptide repeat proteins (DPRs) that have toxic gain-of-function effects; however, the mechanisms by which DPRs lead to neural dysfunction remain unresolved. Here, we observed that poly-proline-arginine (poly-PR) was sufficient to inhibit axonal regeneration of human induced pluripotent stem cell (iPSC)-derived neurons. Global phospho-proteomics revealed that poly-PR selectively perturbs nuclear RNA binding proteins (RBPs). In neurons, we found that depletion of one of these RBPs, SRSF7 (serine/arginine-rich splicing factor 7), resulted in decreased abundance of STMN2 (stathmin-2), though not TDP-43. STMN2 supports axon maintenance and repair and has been recently implicated in the pathogenesis of ALS/FTD. We observed that depletion of SRSF7 impaired axonal regeneration, a phenotype that could be rescued by exogenous STMN2. We propose that antisense repeat-encoded poly-PR perturbs RBPs, particularly SRSF7, resulting in reduced STMN2 and axonal repair defects in neurons. Hence, we provide a potential link between DPRs gain-of-function effects and STMN2 loss-of-function phenotypes in neurodegeneration.

C9ORF72 poly-PR通过SRSF7破坏ALS/ ftd相关STMN2的表达。
C9ORF72的六核苷酸重复扩增是肌萎缩性侧索硬化症(ALS)、额颞叶痴呆(FTD)和ALS/FTD合并的最常见遗传原因。该重复序列沿正反义方向转录,产生几种具有毒性功能获得效应的二肽重复序列蛋白(DPRs);然而,DPRs导致神经功能障碍的机制尚不清楚。在这里,我们观察到聚脯氨酸-精氨酸(poly-PR)足以抑制人诱导多能干细胞(iPSC)来源的神经元轴突再生。全球磷酸化蛋白质组学显示,多聚pr选择性地干扰核RNA结合蛋白(rbp)。在神经元中,我们发现其中一种rbp SRSF7(富含丝氨酸/精氨酸的剪接因子7)的缺失导致STMN2 (stathmin-2)的丰度降低,但TDP-43的丰度不会降低。STMN2支持轴突维持和修复,最近被认为与ALS/FTD的发病机制有关。我们观察到SRSF7的缺失会损害轴突再生,这种表型可以通过外源STMN2来挽救。我们提出反义重复编码的poly-PR干扰rbp,特别是SRSF7,导致神经元中STMN2减少和轴突修复缺陷。因此,我们提供了pprs功能获得效应和STMN2功能丧失表型在神经退行性变中的潜在联系。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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