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 Ingre & 21 others Kevin 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 V Rademakers, Zissimos Mourelatos, Aaron D. Gitler

Research output: Contribution to journalArticle

220 Citations (Scopus)

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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Amyotrophic Lateral Sclerosis
Yeasts
Genes
RNA-Binding Proteins
Prions
Spinal Cord
Genetic Association Studies
Motor Neurons
Computational Biology
Neurodegenerative Diseases
Drosophila
Immunohistochemistry
Neurons
Mutation

ASJC Scopus subject areas

  • General

Cite this

Couthouisa, J., Harta, M. P., Shorter, J., DeJesus-Hernandez, M., Erion, R., Oristano, R., ... 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

A yeast functional screen predicts new candidate ALS disease genes. / Couthouisa, Julien; Harta, 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, Vivianna Deerlin; Rademakers, Rosa V; Mourelatos, Zissimos; Gitler, Aaron D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 52, 27.12.2011, p. 20881-20890.

Research output: Contribution to journalArticle

Couthouisa, J, Harta, MP, Shorter, J, DeJesus-Hernandez, M, Erion, R, Oristano, R, Liu, AX, Ramos, D, Jethava, N, Hosangadi, D, Epstein, J, Chiang, A, Diaz, Z, Nakaya, T, Ibrahim, F, Kim, HJ, Solski, JA, Williams, KL, Mojsilovic-Petrovic, J, Ingre, C, Boylan, K, Graff Radford, NR, Dickson, DW, Clay-Falcone, D, Elman, L, McCluskey, L, Greene, R, Kalb, RG, Lee, VMY, Trojanowski, JQ, Ludolph, A, Robberecht, W, Andersen, PM, Nicholson, GA, Blair, IP, King, OD, Bonini, NM, Van, VD, Rademakers, RV, Mourelatos, Z & Gitler, AD 2011, 'A yeast functional screen predicts new candidate ALS disease genes', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 52, pp. 20881-20890. https://doi.org/10.1073/pnas.1109434108
Couthouisa, Julien ; Harta, 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, Vivianna Deerlin ; Rademakers, Rosa V ; Mourelatos, Zissimos ; Gitler, Aaron D. / A yeast functional screen predicts new candidate ALS disease genes. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 52. pp. 20881-20890.
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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.",
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AU - Couthouisa, Julien

AU - Harta, Michael P.

AU - Shorter, James

AU - DeJesus-Hernandez, Mariely

AU - Erion, Renske

AU - Oristano, Rachel

AU - Liu, Annie X.

AU - Ramos, Daniel

AU - Jethava, Niti

AU - Hosangadi, Divya

AU - Epstein, James

AU - Chiang, Ashley

AU - Diaz, Zamia

AU - Nakaya, Tadashi

AU - Ibrahim, Fadia

AU - Kim, Hyung Jun

AU - Solski, Jennifer A.

AU - Williams, Kelly L.

AU - Mojsilovic-Petrovic, Jelena

AU - Ingre, Caroline

AU - Boylan, Kevin

AU - Graff Radford, Neill R

AU - Dickson, Dennis W

AU - Clay-Falcone, Dana

AU - Elman, Lauren

AU - McCluskey, Leo

AU - Greene, Robert

AU - Kalb, Robert G.

AU - Lee, Virginia M Y

AU - Trojanowski, John Q.

AU - Ludolph, Albert

AU - Robberecht, Wim

AU - Andersen, Peter M.

AU - Nicholson, Garth A.

AU - Blair, Ian P.

AU - King, Oliver D.

AU - Bonini, Nancy M.

AU - Van, Vivianna Deerlin

AU - Rademakers, Rosa V

AU - Mourelatos, Zissimos

AU - Gitler, Aaron D.

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N2 - 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.

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