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Title: A yeast functional screen predicts new candidate ALS disease genes
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 # ×
Issue Date: Dec-2011
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:108 issue:52 pages:20881-90
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.
URI: 
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neurobiology (Vesalius Research Center)
× corresponding author
# (joint) last author

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