title: A yeast functional screen predicts new candidate ALS disease genes.
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.
authors: Departments of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D019295:Computational Biology; D004331:Drosophila melanogaster / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D009046:Motor Neurons / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology*; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D016601:RNA-Binding Proteins; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors