title: ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP.
abstract: The RNA-binding protein FUS/TLS, mutation in which is causative of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), is demonstrated to directly bind to the U1-snRNP and SMN complexes. ALS-causative mutations in FUS/TLS are shown to abnormally enhance their interaction with SMN and dysregulate its function, including loss of Gems and altered levels of small nuclear RNAs. The same mutants are found to have reduced association with U1-snRNP. Correspondingly, global RNA analysis reveals a mutant-dependent loss of splicing activity, with ALS-linked mutants failing to reverse changes caused by loss of wild-type FUS/TLS. Furthermore, a common FUS/TLS mutant-associated RNA splicing signature is identified in ALS patient fibroblasts. Taken together, these studies establish potentially converging disease mechanisms in ALS and spinal muscular atrophy, with ALS-causative mutants acquiring properties representing both gain (dysregulation of SMN) and loss (reduced RNA processing mediated by U1-snRNP) of function.
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Shuying
authors.initials: S
authors.lastname: Sun
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.|Department of Physiology, National University of Singapore, 14 Medical Drive, Singapore 117599.
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Claudio P
authors.initials: CP
authors.lastname: Albuquerque
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Seiya
authors.initials: S
authors.lastname: Tokunaga
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Hairi
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, University of California at San Francisco, San Francisco, CA 94143.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Anh
authors.initials: A
authors.lastname: Bui
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.|Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Department of Pathology, University of California at San Francisco, San Francisco, CA 94143.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.|Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lagier-Tourenne
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093.|Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000596:Amino Acids / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D002846:Chromatography, Affinity; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D007553:Isotope Labeling; D008822:Mice, Transgenic; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D040901:Proteomics; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000378:metabolism*; D055532:SMN Complex Proteins / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D000596:Amino Acids; D050505:Mutant Proteins; D012322:RNA Precursors; D034702:RNA-Binding Protein FUS; D017412:Ribonucleoprotein, U1 Small Nuclear; D055532:SMN Complex Proteins