yeast functional screen predicts new candidate ALS disease genes

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-12, Vol.108 (52), p.20881-20890
• Main Authors: Couthouis, Julien, Hart, Michael P, Shorter, James, DeJesus-Hernandez, Mariely, Erion, Renske, Oristano, Rachel, Liu, Annie X, Ramos, Daniel, Jethava, Niti, Hosangadi, Divya, Epstein, James, Chiang, Ashley, Diaz, Zamia, Nakaya, Tadashi, Ibrahim, Fadia, Kim, Hyung-Jun, Solski, Jennifer A, Williams, Kelly L, Mojsilovic-Petrovic, Jelena, Ingre, Caroline, Boylan, Kevin, Graff-Radford, Neill R, Dickson, Dennis W, Clay-Falcone, Dana, Elman, Lauren, McCluskey, Leo, Greene, Robert, Kalb, Robert G, Lee, Virginia M.-Y, Trojanowski, John Q, Ludolph, Albert, Robberecht, Wim, Andersen, Peter M, Nicholson, Garth A, Blair, Ian P, King, Oliver D, Bonini, Nancy M, Van Deerlin, Vivianna, Rademakers, Rosa, Mourelatos, Zissimos, Gitler, Aaron D
• Format: Article
• Language: English
• Subjects: Aggregation; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Animals; Bioinformatics; Biological Sciences; Cells, Cultured; Computational Biology; Drosophila; Drosophila melanogaster - genetics; FUS protein; Genes; Genetic Association Studies - methods; Genetic mutation; Humans; Immunohistochemistry; Medicin och hälsovetenskap; Motor neurons; Motor Neurons - metabolism; Mutation; Mutation, Missense - genetics; Nervous system diseases; Neurodegenerative diseases; Neurons; pathogenesis; patients; prediction; Prions; Protein Structure, Tertiary; Proteins; Ribonucleic acid; RNA; RNA-binding protein; RNA-binding proteins; RNA-Binding Proteins - genetics; Saccharomyces cerevisiae - genetics; sclerosis; Spinal cord; Spinal Cord - cytology; surveys; TATA-Binding Protein Associated Factors - genetics; TATA-Binding Protein Associated Factors - metabolism; Yeast; Yeasts
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1109434108

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.