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.