A yeast functional screen predicts new candidate ALS disease genes

Julien Couthouisa, Michael P. Harta, James Shorter, Mariely DeJesus-Hernandez, Renske Erion, Rachel Oristano, Annie X. Liu, Daniel Ramos, Niti Jethava, Divya Hosangadi, James Epstein, Ashley Chiang, Zamia Diaz, Tadashi Nakaya, Fadia Ibrahim, Hyung Jun Kim, Jennifer A. Solski, Kelly L. Williams, Jelena Mojsilovic-Petrovic, Caroline IngreKevin Boylan, Neill R. Graff-Radford, Dennis W. Dickson, Dana Clay-Falcone, Lauren Elman, Leo McCluskey, Robert Greene, Robert G. Kalb, Virginia M.Y. Lee, John Q. Trojanowski, Albert Ludolph, Wim Robberecht, Peter M. Andersen, Garth A. Nicholson, Ian P. Blair, Oliver D. King, Nancy M. Bonini, Vivianna Deerlin Van, Rosa Rademakers, Zissimos Mourelatos, Aaron D. Gitler

Research output: Contribution to journalArticle

237 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20881-20890
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number52
DOIs
StatePublished - Dec 27 2011

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Couthouisa, J., Harta, M. P., Shorter, J., DeJesus-Hernandez, M., Erion, R., Oristano, R., Liu, A. X., Ramos, D., Jethava, N., Hosangadi, D., Epstein, J., Chiang, A., Diaz, Z., Nakaya, T., Ibrahim, F., Kim, H. J., Solski, J. A., Williams, K. L., Mojsilovic-Petrovic, J., ... Gitler, A. D. (2011). A yeast functional screen predicts new candidate ALS disease genes. Proceedings of the National Academy of Sciences of the United States of America, 108(52), 20881-20890. https://doi.org/10.1073/pnas.1109434108