U1 snRNP is mislocalized in ALS patient fibroblasts bearing NLS mutations in FUS and is required for motor neuron outgrowth in zebrafish

Yu, Y., Chi, B., Xia, W., Gangopadhyay, J., Yamazaki, T., Winkelbauer-Hurt, M.E., Yin, S., Eliasse, Y., Adams, E., Shaw, C.E., Reed, R.
Nucleic acids research   43(6): 3208-18 (Journal)
Registered Authors
MeSH Terms
  • Amyotrophic Lateral Sclerosis/genetics*
  • Amyotrophic Lateral Sclerosis/metabolism*
  • Amyotrophic Lateral Sclerosis/pathology
  • Animals
  • Animals, Genetically Modified
  • Cytoplasm/metabolism
  • Gemini of Coiled Bodies/metabolism
  • Gemini of Coiled Bodies/pathology
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Motor Neurons/metabolism
  • Motor Neurons/pathology
  • Mutation
  • Nuclear Localization Signals/genetics*
  • Protein Interaction Domains and Motifs
  • RNA-Binding Protein FUS/chemistry
  • RNA-Binding Protein FUS/genetics*
  • RNA-Binding Protein FUS/metabolism
  • Recombinant Proteins/chemistry
  • Recombinant Proteins/genetics
  • Recombinant Proteins/metabolism
  • Ribonucleoprotein, U1 Small Nuclear/antagonists & inhibitors
  • Ribonucleoprotein, U1 Small Nuclear/genetics
  • Ribonucleoprotein, U1 Small Nuclear/metabolism*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • snRNP Core Proteins/genetics
  • snRNP Core Proteins/metabolism
25735748 Full text @ Nucleic Acids Res.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes