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

• Published in: Cell reports (Cambridge) Vol. 2; no. 4; pp. 799 - 806
• Main Authors: Yamazaki, Tomohiro, Chen, Shi, Yu, Yong, Yan, Biao, Haertlein, Tyler C., Carrasco, Monica A., Tapia, Juan C., Zhai, Bo, Das, Rita, Lalancette-Hebert, Melanie, Sharma, Aarti, Chandran, Siddharthan, Sullivan, Gareth, Nishimura, Agnes Lumi, Shaw, Christopher E., Gygi, Steve P., Shneider, Neil A., Maniatis, Tom, Reed, Robin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.10.2012; Elsevier
• Subjects: Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; DEAD Box Protein 20 - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; HeLa Cells; Humans; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Mutation; Ribonucleoproteins, Small Nuclear - metabolism; RNA Interference; RNA, Small Interfering - metabolism; RNA-Binding Protein FUS - antagonists & inhibitors; RNA-Binding Protein FUS - genetics; RNA-Binding Protein FUS - metabolism; SMN Complex Proteins - genetics; SMN Complex Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.08.025

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. [Display omitted] ► A shared molecular pathway is altered in ALS and SMA motor neuron diseases ► ALS and SMA proteins FUS and SMN physically and functionally interact ► Gems are deficient in human ALS patient fibroblasts Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are fatal adult and childhood motor neuron diseases, respectively, that share clinical features. Reed and colleagues now find that the protein FUS, which is mutated in ALS, associates with SMN, the protein that is deficient in SMA. SMN resides in nuclear bodies known as Gems, and lack of Gems is a cellular hallmark of SMA. Remarkably, Gem deficiency is also observed in ALS patient fibroblasts. This work thus provides biochemical evidence that ALS and SMA share a common pathway.