ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP

Shuying Sun, Shuo Chien Ling, Jinsong Qiu, Claudio P. Albuquerque, Yu Zhou, Seiya Tokunaga, Hairi Li, Haiyan Qiu, Anh Bui, Gene W. Yeo, Eric J. Huang, Kevin Eggan, Huilin Zhou, Xiang Dong Fu, Clotilde Lagier-Tourenne, Don W. Cleveland

Research output: Contribution to journalArticle

Abstract

The RNA-binding protein FUS/TLS, mutation in which is causative of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), is demonstrated to directly bind to the U1-snRNP and SMN complexes. ALS-causative mutations in FUS/TLS are shown to abnormally enhance their interaction with SMN and dysregulate its function, including loss of Gems and altered levels of small nuclear RNAs. The same mutants are found to have reduced association with U1-snRNP. Correspondingly, global RNA analysis reveals a mutant-dependent loss of splicing activity, with ALS-linked mutants failing to reverse changes caused by loss of wild-type FUS/TLS. Furthermore, a common FUS/TLS mutant-associated RNA splicing signature is identified in ALS patient fibroblasts. Taken together, these studies establish potentially converging disease mechanisms in ALS and spinal muscular atrophy, with ALS-causative mutants acquiring properties representing both gain (dysregulation of SMN) and loss (reduced RNA processing mediated by U1-snRNP) of function.

Original languageEnglish (US)
Article number6171
JournalNature Communications
Volume6
DOIs
StatePublished - 2015
Externally publishedYes

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U1 Small Nuclear Ribonucleoproteins
Amyotrophic Lateral Sclerosis
mutations
splicing
Mutation
RNA
RNA-Binding Protein FUS
SMN Complex Proteins
atrophy
Gems
Small Nuclear RNA
fibroblasts
Fibroblasts
neurons
Neurons
RNA Splicing
Spinal Muscular Atrophy
signatures
proteins
Processing

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. / Sun, Shuying; Ling, Shuo Chien; Qiu, Jinsong; Albuquerque, Claudio P.; Zhou, Yu; Tokunaga, Seiya; Li, Hairi; Qiu, Haiyan; Bui, Anh; Yeo, Gene W.; Huang, Eric J.; Eggan, Kevin; Zhou, Huilin; Fu, Xiang Dong; Lagier-Tourenne, Clotilde; Cleveland, Don W.

In: Nature Communications, Vol. 6, 6171, 2015.

Research output: Contribution to journalArticle

Sun, S, Ling, SC, Qiu, J, Albuquerque, CP, Zhou, Y, Tokunaga, S, Li, H, Qiu, H, Bui, A, Yeo, GW, Huang, EJ, Eggan, K, Zhou, H, Fu, XD, Lagier-Tourenne, C & Cleveland, DW 2015, 'ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP', Nature Communications, vol. 6, 6171. https://doi.org/10.1038/ncomms7171
Sun, Shuying ; Ling, Shuo Chien ; Qiu, Jinsong ; Albuquerque, Claudio P. ; Zhou, Yu ; Tokunaga, Seiya ; Li, Hairi ; Qiu, Haiyan ; Bui, Anh ; Yeo, Gene W. ; Huang, Eric J. ; Eggan, Kevin ; Zhou, Huilin ; Fu, Xiang Dong ; Lagier-Tourenne, Clotilde ; Cleveland, Don W. / ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. In: Nature Communications. 2015 ; Vol. 6.
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abstract = "The RNA-binding protein FUS/TLS, mutation in which is causative of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), is demonstrated to directly bind to the U1-snRNP and SMN complexes. ALS-causative mutations in FUS/TLS are shown to abnormally enhance their interaction with SMN and dysregulate its function, including loss of Gems and altered levels of small nuclear RNAs. The same mutants are found to have reduced association with U1-snRNP. Correspondingly, global RNA analysis reveals a mutant-dependent loss of splicing activity, with ALS-linked mutants failing to reverse changes caused by loss of wild-type FUS/TLS. Furthermore, a common FUS/TLS mutant-associated RNA splicing signature is identified in ALS patient fibroblasts. Taken together, these studies establish potentially converging disease mechanisms in ALS and spinal muscular atrophy, with ALS-causative mutants acquiring properties representing both gain (dysregulation of SMN) and loss (reduced RNA processing mediated by U1-snRNP) of function.",
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AU - Albuquerque, Claudio P.

AU - Zhou, Yu

AU - Tokunaga, Seiya

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AU - Bui, Anh

AU - Yeo, Gene W.

AU - Huang, Eric J.

AU - Eggan, Kevin

AU - Zhou, Huilin

AU - Fu, Xiang Dong

AU - Lagier-Tourenne, Clotilde

AU - Cleveland, Don W.

PY - 2015

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AB - The RNA-binding protein FUS/TLS, mutation in which is causative of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), is demonstrated to directly bind to the U1-snRNP and SMN complexes. ALS-causative mutations in FUS/TLS are shown to abnormally enhance their interaction with SMN and dysregulate its function, including loss of Gems and altered levels of small nuclear RNAs. The same mutants are found to have reduced association with U1-snRNP. Correspondingly, global RNA analysis reveals a mutant-dependent loss of splicing activity, with ALS-linked mutants failing to reverse changes caused by loss of wild-type FUS/TLS. Furthermore, a common FUS/TLS mutant-associated RNA splicing signature is identified in ALS patient fibroblasts. Taken together, these studies establish potentially converging disease mechanisms in ALS and spinal muscular atrophy, with ALS-causative mutants acquiring properties representing both gain (dysregulation of SMN) and loss (reduced RNA processing mediated by U1-snRNP) of function.

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