Journal
HUMAN MOLECULAR GENETICS
Volume 22, Issue 13, Pages 2676-2688Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt117
Keywords
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Funding
- American ALS Association
- Middlemass family
- Lady Edith Wolfson Trust
- Motor Neurone Disease Association UK
- Wellcome Trust
- European Union (APOPIS consortium) [LSHM-CT-2003-503330]
- European Union (NeuroNE Consortium)
- European Union (Marie Curie International Incoming Fellowship)
- NIHR Biomedical Research Centre for Mental Health
- South London and Maudsley NHS Foundation Trust
- Medical Research Council UK
- King's College Hospital Charity
- Psychiatry Research Trust of the Institute of Psychiatry
- Coker Charitable Trust
- Health Research Council of New Zealand
- Medical Research Council [G0900688, MC_G1000733, G1100695, G0501573] Funding Source: researchfish
- MRC [G1100695, G0900688, G0501573, MC_G1000733] Funding Source: UKRI
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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 proteinprotein 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.
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