Disruption of nuclear speckle integrity dysregulates RNA splicing in C9ORF72-FTD/ALS

被引：3

作者：

Wu, Rong ^{[1
,2
]}

Ye, Yingzhi ^{[1
,2
,3
]}

Dong, Daoyuan ^{[1
,2
]}

Zhang, Zhe ^{[1
,2
]}

Wang, Shaopeng ^{[1
,2
,4
]}

Li, Yini ^{[1
,2
]}

Wright, Noelle ^{[1
,2
]}

Redding-Ochoa, Javier ^{[5
,6
]}

Chang, Koping ^{[5
]}

Xu, Shaohai ^{[7
,12
]}

Tu, Xueting ^{[1
,2
]}

Zhu, Chengzhang ^{[1
,2
,8
]}

Ostrow, Lyle W. ^{[9
]}

Roca, Xavier ^{[7
]}

Troncoso, Juan C. ^{[5
,6
]}

Wu, Bin ^{[4
,10
,11
]}

Sun, Shuying ^{[1
,2
,5
,10
,11
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Brain Sci Inst, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Cellular & Mol Physiol Grad Program, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[7] Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore

[8] Johns Hopkins Univ, Sch Med, Cellular & Mol Med Grad Program, Baltimore, MD 21205 USA

[9] Temple Univ, Lewis Katz Sch Med, Dept Neurol, Philadelphia, PA 19122 USA

[10] Johns Hopkins Univ, Sch Med, Ctr Cell Dynam, Baltimore, MD 21205 USA

[11] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA

[12] Natl Univ Singapore, Duke NUS Med Sch, Ctr Vis Res, Singapore 169857, Singapore

来源：

NEURON | 2024年 / 112卷 / 20期

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; DIPEPTIDE-REPEAT PROTEINS; IN-VIVO; HEXANUCLEOTIDE REPEAT; GGGGCC REPEAT; LIVING CELLS; C9ORF72; ALS; EXPANSION; TDP-43;

D O I：

10.1016/j.neuron.2024.07.025

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Expansion of an intronic (GGGGCC)n repeat within the C9ORF72 gene is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (C9-FTD/ALS), characterized with aberrant repeat RNA foci and noncanonical translation-produced dipeptide repeat (DPR) protein inclusions. Here, we elucidate that the (GGGGCC)n repeat RNA co-localizes with nuclear speckles and alters their phase separation properties and granule dynamics. Moreover, the essential nuclear speckle scaffold protein SRRM2 is sequestered into the poly-GR cytoplasmic inclusions in the C9-FTD/ALS mouse model and patient postmortem tissues, exacerbating the nuclear speckle dysfunction. Impaired nuclear speckle integrity induces global exon skipping and intron retention in human iPSC-derived neurons and causes neuronal toxicity. Similar alternative splicing changes can be found in C9-FTD/ALS patient postmortem tissues. This work identified novel molecular mechanisms of global RNA splicing defects caused by impaired nuclear speckle function in C9-FTD/ALS and revealed novel potential biomarkers or therapeutic targets.

引用

页码：3434 / 3451.e11

页数：30

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