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

共 96 条

[1] Correction of amyotrophic lateral sclerosis related phenotypes in induced pluripotent stem cell-derived motor neurons carrying a hexanucleotide expansion mutation in C9orf72 by CRISPR/Cas9 genome editing using homology-directed repair [J].

Ababneh, Nidaa A. ;

Scaber, Jakub ;

Flynn, Rowan ;

Douglas, Andrew ;

Barbagallo, Paola ;

Candalija, Ana ;

Turner, Martin R. ;

Sims, David ;

Dafinca, Ruxandra ;

Cowley, Sally A. ;

Talbot, Kevin .

HUMAN MOLECULAR GENETICS, 2020, 29 (13) :2200-2217

[2] U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease [J].

Bai, Bing ;

Hales, Chadwick M. ;

Chen, Ping-Chung ;

Gozal, Yair ;

Dammer, Eric B. ;

Fritz, Jason J. ;

Wang, Xusheng ;

Xia, Qiangwei ;

Duong, Duc M. ;

Street, Craig ;

Cantero, Gloria ;

Cheng, Dongmei ;

Jones, Drew R. ;

Wu, Zhiping ;

Li, Yuxin ;

Diner, Ian ;

Heilman, Craig J. ;

Rees, Howard D. ;

Wu, Hao ;

Lin, Li ;

Szulwach, Keith E. ;

Gearing, Marla ;

Mufson, Elliott J. ;

Bennett, David A. ;

Montine, Thomas J. ;

Seyfried, Nicholas T. ;

Wingo, Thomas S. ;

Sun, Yi E. ;

Jin, Peng ;

Hanfelt, John ;

Willcock, Donna M. ;

Levey, Allan ;

Lah, James J. ;

Peng, Junmin .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (41) :16562-16567

[3] The MEME Suite [J].

Bailey, Timothy L. ;

Johnson, James ;

Grant, Charles E. ;

Noble, William S. .

NUCLEIC ACIDS RESEARCH, 2015, 43 (W1) :W39-W49

[4] Nuclear Compartments: An Incomplete Primer to Nuclear Compartments, Bodies, and Genome Organization Relative to Nuclear Architecture [J].

Belmont, Andrew S. .

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2022, 14 (07)

[5] Genome organization around nuclear speckles drives mRNA splicing efficiency [J].

Bhat, Prashant ;

Chow, Amy ;

Emert, Benjamin ;

Ettlin, Olivia ;

Quinodoz, Sofia A. ;

Strehle, Mackenzie ;

Takei, Yodai ;

Burr, Alex ;

Goronzy, Isabel N. ;

Chen, Allen W. ;

Huang, Wesley ;

Ferrer, Jose Lorenzo M. ;

Soehalim, Elizabeth ;

Goh, Say-Tar ;

Chari, Tara ;

Sullivan, Delaney K. ;

Blanco, Mario R. ;

Guttman, Mitchell .

NATURE, 2024, 629 (8014) :1165-1173

[6] RBM25 is a global splicing factor promoting inclusion of alternatively spliced exons and is itself regulated by lysine mono-methylation [J].

Carlson, Scott M. ;

Soulette, Cameron M. ;

Yang, Ze ;

Elias, Joshua E. ;

Brooks, Angela N. ;

Gozani, Or .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2017, 292 (32) :13381-13390

[7] Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106 [J].

Celona, Barbara ;

von Dollen, John ;

Vatsavayai, Sarat C. ;

Kashima, Risa ;

Johnson, Jeffrey R. ;

Tang, Amy A. ;

Hata, Akiko ;

Miller, Bruce L. ;

Huang, Eric J. ;

Krogan, Nevan J. ;

Seeley, William W. ;

Black, Brian L. .

ELIFE, 2017, 6

[8] Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [J].

Chen, Ping-Chung ;

Han, Xian ;

Shaw, Timothy I. ;

Fu, Yingxue ;

Sun, Huan ;

Niu, Mingming ;

Wang, Zhen ;

Jiao, Yun ;

Teubner, Brett J. W. ;

Eddins, Donnie ;

Beloate, Lauren N. ;

Bai, Bing ;

Mertz, Joseph ;

Li, Yuxin ;

Cho, Ji-Hoon ;

Wang, Xusheng ;

Wu, Zhiping ;

Liu, Danting ;

Poudel, Suresh ;

Yuan, Zuo-Fei ;

Mancieri, Ariana ;

Low, Jonathan ;

Lee, Hyeong-Min ;

Patton, Mary H. ;

Earls, Laurie R. ;

Stewart, Elizabeth ;

Vogel, Peter ;

Hui, Yawei ;

Wan, Shibiao ;

Bennett, David A. ;

Serrano, Geidy E. ;

Beach, Thomas G. ;

Dyer, Michael A. ;

Smeyne, Richard J. ;

Moldoveanu, Tudor ;

Chen, Taosheng ;

Wu, Gang ;

Zakharenko, Stanislav S. ;

Yu, Gang ;

Peng, Junmin .

NATURE AGING, 2022, 2 (10) :923-+

[9] Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy [J].

Chew, Jeannie ;

Cook, Casey ;

Gendron, Tania F. ;

Jansen-West, Karen ;

del Rosso, Giulia ;

Daughrity, Lillian M. ;

Castanedes-Casey, Monica ;

Kurti, Aishe ;

Stankowski, Jeannette N. ;

Disney, Matthew D. ;

Rothstein, Jeffrey D. ;

Dickson, Dennis W. ;

Fryer, John D. ;

Zhang, Yong-Jie ;

Petrucelli, Leonard .

MOLECULAR NEURODEGENERATION, 2019, 14 (1)

[10] C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits [J].

Chew, Jeannie ;

Gendron, Tania F. ;

Prudencio, Mercedes ;

Sasaguri, Hiroki ;

Zhang, Yong-Jie ;

Castanedes-Casey, Monica ;

Lee, ChrisW. ;

Jansen-West, Karen ;

Kurti, Aishe ;

Murray, Melissa E. ;

Bieniek, Kevin F. ;

Bauer, Peter O. ;

Whitelaw, Ena C. ;

Rousseau, Linda ;

Stankowski, Jeannette N. ;

Stetler, Caroline ;

Daughrity, Lillian M. ;

Perkerson, Emilie A. ;

Desaro, Pamela ;

Johnston, Amelia ;

Overstreet, Karen ;

Edbauer, Dieter ;

Rademakers, Rosa ;

Boylan, Kevin B. ;

Dickson, Dennis W. ;

Fryer, John D. ;

Petrucelli, Leonard .

SCIENCE, 2015, 348 (6239) :1151-1154

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