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001-es BibID:BIBFORM051631
035-os BibID:PMID: 23474818
Első szerző:Vance, Caroline
Cím: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, Tibor Hortobágyi, Mike Dragunow, Boris Rogelj, Christopher E. Shaw
Dátum:2013
ISSN:0964-6906
Megjegyzések: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.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Human Molecular Genetics. - 22 : 13 (2013), p. 2676-2688. -
További szerzők:Scotter, Emma L. Nishimura, Agnes Lumi Troakes, Claire Mitchell, Jacqueline C. Kathe, Claudia Urwin, Hazel Manser, Catherine Miller, Christopher C. Hortobágyi Tibor (1965-) (patológus) Dragunow, Mike Rogelj, Boris Shaw, Christopher E.
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