title: FUS-SMN protein interactions link the motor neuron diseases ALS and SMA.
abstract: Mutations in the RNA binding protein FUS cause amyotrophic lateral sclerosis (ALS), a fatal adult motor neuron disease. Decreased expression of SMN causes the fatal childhood motor neuron disorder spinal muscular atrophy (SMA). The SMN complex localizes in both the cytoplasm and nuclear Gems, and loss of Gems is a cellular hallmark of fibroblasts in patients with SMA. Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN. Functionally, we show that FUS is required for Gem formation in HeLa cells, and expression of FUS containing a severe ALS-causing mutation (R495X) also results in Gem loss. Strikingly, a reduction in Gems is observed in ALS patient fibroblasts expressing either mutant FUS or TDP-43, another ALS-causing protein that interacts with FUS. The physical and functional interactions among SMN, FUS, TDP-43, and Gems indicate that ALS and SMA share a biochemical pathway, providing strong support for the view that these motor neuron diseases are related.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.forename: Biao
authors.initials: B
authors.lastname: Yan
authors.forename: Tyler C
authors.initials: TC
authors.lastname: Haertlein
authors.forename: Monica A
authors.initials: MA
authors.lastname: Carrasco
authors.forename: Juan C
authors.initials: JC
authors.lastname: Tapia
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Rita
authors.initials: R
authors.lastname: Das
authors.forename: Melanie
authors.initials: M
authors.lastname: Lalancette-Hebert
authors.forename: Aarti
authors.initials: A
authors.lastname: Sharma
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
authors.forename: Gareth
authors.initials: G
authors.lastname: Sullivan
authors.forename: Agnes Lumi
authors.initials: AL
authors.lastname: Nishimura
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Steve P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Neil A
authors.initials: NA
authors.lastname: Shneider
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
authors.forename: Robin
authors.initials: R
authors.lastname: Reed
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D055541:DEAD Box Protein 20 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D055532:SMN Complex Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D034702:RNA-Binding Protein FUS; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins; D055541:DEAD Box Protein 20