FUS-SMN Protein Interactions Link the Motor Neuron Diseases ALS and SMA

• DOI: 10.1016/j.celrep.2012.08.025
• Publication Date: 2012-09-27T11:23:47Z
• Authors: Tomohiro Yamazaki; Shi Chen; Yong Yu; Biao Yan; Tyler C. Haertlein; Monica A. Carrasco; Juan C. Tapia; Bo Zhai; Rita Das; Melanie Lalancett...; Aarti Sharma; Siddharthan Chandran; Gareth Sullivan; Agnes Lumi Nishimura; Christopher E. Shaw; Steve P. Gygi; Neil A. Shneider; Tom Maniatis; Robin Reed
• Keywords: Spinal; TDP-43; QH301-705.5; 610; Small Interfering; AMYOTROPHIC-LATERAL-SCLEROSIS; Muscular Atrophy, Spinal; 03 medical and health sciences; Small Nuclear; DEAD Box Protein 20; Humans; Biology (General); RNA, Small Interfering; 0303 health sciences; COMPLEX; HEXANUCLEOTIDE REPEAT; IDENTIFICATION; MUTATIONS; SPINAL MUSCULAR-ATROPHY; Amyotrophic Lateral Sclerosis; SMN Complex Proteins; Ribonucleoproteins, Small Nuclear; DNA-Binding Proteins; Muscular Atrophy; Ribonucleoproteins; Mutation; SURVIVAL; RNA; RNA-Binding Protein FUS; RNA Interference; MESSENGER-RNA; FUS/TLS; HeLa Cells

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.