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U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish.
Yu, Yong; Chi, Binkai; Xia, Wei; Gangopadhyay, Jaya; Yamazaki, Tomohiro; Winkelbauer-Hurt, Marlene E; Yin, Shanye; Eliasse, Yoan; Adams, Edward; Shaw, Christopher E; Reed, Robin.
Afiliação
  • Yu Y; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
  • Chi B; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
  • Xia W; Department of Marine Biotechnology, University of Maryland Baltimore County & Institute of Marine and Environmental Technology, Baltimore, MD 21042, USA.
  • Gangopadhyay J; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
  • Yamazaki T; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
  • Winkelbauer-Hurt ME; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
  • Yin S; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
  • Eliasse Y; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
  • Adams E; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
  • Shaw CE; King's College London and King's Health Partners, MRC Centre for Neurodegeneration Research, London SE5 8AF, UK.
  • Reed R; Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA rreed@hms.harvard.edu.
Nucleic Acids Res ; 43(6): 3208-18, 2015 Mar 31.
Article em En | MEDLINE | ID: mdl-25735748
Mutations in FUS cause amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to neurodegeneration remain obscure. We previously found that U1 snRNP is the most abundant FUS interactor. Here, we report that components of the U1 snRNP core particle (Sm proteins and U1 snRNA), but not the mature U1 snRNP-specific proteins (U1-70K, U1A and U1C), co-mislocalize with FUS to the cytoplasm in ALS patient fibroblasts harboring mutations in the FUS nuclear localization signal (NLS). Similar results were obtained in HeLa cells expressing the ALS-causing FUS R495X NLS mutation, and mislocalization of Sm proteins is RRM-dependent. Moreover, as observed with FUS, knockdown of any of the U1 snRNP-specific proteins results in a dramatic loss of SMN-containing Gems. Significantly, knockdown of U1 snRNP in zebrafish results in motor axon truncations, a phenotype also observed with FUS, SMN and TDP-43 knockdowns. Our observations linking U1 snRNP to ALS patient cells with FUS mutations, SMN-containing Gems, and motor neurons indicate that U1 snRNP is a component of a molecular pathway associated with motor neuron disease. Linking an essential canonical splicing factor (U1 snRNP) to this pathway provides strong new evidence that splicing defects may be involved in pathogenesis and that this pathway is a potential therapeutic target.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ribonucleoproteína Nuclear Pequena U1 / Sinais de Localização Nuclear / Proteína FUS de Ligação a RNA / Esclerose Lateral Amiotrófica Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ribonucleoproteína Nuclear Pequena U1 / Sinais de Localização Nuclear / Proteína FUS de Ligação a RNA / Esclerose Lateral Amiotrófica Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article