Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS

被引：93

作者：

Rossi, Simona ^{[1
,2
,3
]}

Serrano, Alessia ^{[1
]}

Gerbino, Valeria ^{[2
,3
]}

Giorgi, Alessandra ^{[4
]}

Di Francesco, Laura ^{[4
]}

Nencini, Monica ^{[2
]}

Bozzo, Francesca ^{[2
,3
]}

Schinina, Maria Eugenia ^{[4
]}

Bagni, Claudia ^{[5
,6
,7
]}

Cestra, Gianluca ^{[8
,9
]}

Carri, Maria Teresa ^{[2
,3
]}

Achsel, Tilmann ^{[6
,7
]}

Cozzolino, Mauro ^{[1
,2
]}

机构：

[1] CNR, Inst Translat Pharmacol, I-00133 Rome, Italy

[2] Fdn Santa Lucia IRCCS, Lab Neurochem, I-00143 Rome, Italy

[3] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

[4] Univ Roma La Sapienza, Dept Biochem Sci Rossi Fanelli, I-00185 Rome, Italy

[5] Univ Roma Tor Vergata, Dept Biomed & Prevent, I-00133 Rome, Italy

[6] Katholieke Univ Leuven, Ctr Human Genet, B-3000 Louvain, Belgium

[7] VIB Ctr Biol Dis, B-3000 Louvain, Belgium

[8] CNR, Inst Mol Biol & Pathol, I-00185 Rome, Italy

[9] Univ Roma La Sapienza, Dept Biol & Biotechnol Charles Darwin, I-00185 Rome, Italy

来源：

JOURNAL OF CELL SCIENCE | 2015年 / 128卷 / 09期

关键词：

Amyotrophic lateral sclerosis; C9orf72; Stress granules; mRNA; AMYOTROPHIC-LATERAL-SCLEROSIS; HEXANUCLEOTIDE REPEAT EXPANSION; POLY(A)-BINDING PROTEINS; FRONTOTEMPORAL DEMENTIA; GENE-EXPRESSION; STRESS GRANULES; BINDING-PROTEIN; DISEASE; MECHANISMS; NEURODEGENERATION;

D O I：

10.1242/jcs.165332

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)(31) repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)(31) repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS.

引用

页码：1787 / 1799

页数：13

共 33 条

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