ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules

Caroline Vance, Emma L. Scotter, Agnes L. Nishimura, Claire Troakes, Jacqueline C. Mitchell, Claudia Kathe, Hazel Urwin, Catherine Manser, Christopher C. Miller, T. Hortobágyi, Mike Dragunow, Boris Rogelj, Christopher E. Shaw

Research output: Contribution to journalArticle

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Abstract

Mutations in the gene encoding Fused in Sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. FUS is a predominantly nuclear DNA- and RNA-binding protein that is involved in RNA processing. Large FUS-immunoreactive inclusions fill the perikaryon of surviving motor neurons of ALS patients carrying mutations at post-mortem. This sequestration of FUS is predicted to disrupt RNA processing and initiate neurodegeneration. Here, we demonstrate that C-terminal ALS mutations disrupt the nuclear localizing signal (NLS) of FUS resulting in cytoplasmic accumulation in transfected cells and patient fibroblasts. FUS mislocalization is rescued by the addition of the wild-type FUS NLS to mutant proteins. We also show that oxidative stress recruits mutant FUS to cytoplasmic stress granules where it is able to bind and sequester wild-type FUS. While FUS interacts with itself directly by protein-protein interaction, the recruitment of FUS to stress granules and interaction with PABP are RNA dependent. These findings support a two-hit hypothesis, whereby cytoplasmic mislocalization of FUS protein, followed by cellular stress, contributes to the formation of cytoplasmic aggregates that may sequester FUS, disrupt RNA processing and initiate motor neuron degeneration.

Original languageEnglish
Pages (from-to)2676-2688
Number of pages13
JournalHuman Molecular Genetics
Volume22
Issue number13
DOIs
Publication statusPublished - Jul 2013

Fingerprint

Cytoplasmic Granules
Amyotrophic Lateral Sclerosis
Sarcoma
RNA
Motor Neurons
Mutation
Nuclear RNA
Nerve Degeneration
Proteins
RNA-Binding Proteins
DNA-Binding Proteins
Mutant Proteins
Nuclear Proteins
Neurodegenerative Diseases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Vance, C., Scotter, E. L., Nishimura, A. L., Troakes, C., Mitchell, J. C., Kathe, C., ... Shaw, C. E. (2013). ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules. Human Molecular Genetics, 22(13), 2676-2688. https://doi.org/10.1093/hmg/ddt117

ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules. / Vance, Caroline; Scotter, Emma L.; Nishimura, Agnes L.; Troakes, Claire; Mitchell, Jacqueline C.; Kathe, Claudia; Urwin, Hazel; Manser, Catherine; Miller, Christopher C.; Hortobágyi, T.; Dragunow, Mike; Rogelj, Boris; Shaw, Christopher E.

In: Human Molecular Genetics, Vol. 22, No. 13, 07.2013, p. 2676-2688.

Research output: Contribution to journalArticle

Vance, C, Scotter, EL, Nishimura, AL, Troakes, C, Mitchell, JC, Kathe, C, Urwin, H, Manser, C, Miller, CC, Hortobágyi, T, Dragunow, M, Rogelj, B & Shaw, CE 2013, 'ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules', Human Molecular Genetics, vol. 22, no. 13, pp. 2676-2688. https://doi.org/10.1093/hmg/ddt117
Vance, Caroline ; Scotter, Emma L. ; Nishimura, Agnes L. ; Troakes, Claire ; Mitchell, Jacqueline C. ; Kathe, Claudia ; Urwin, Hazel ; Manser, Catherine ; Miller, Christopher C. ; Hortobágyi, T. ; Dragunow, Mike ; Rogelj, Boris ; Shaw, Christopher E. / ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 13. pp. 2676-2688.
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