A yeast functional screen predicts new candidate ALS disease genes

作者：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

来源：Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(52): 20881-20890.

DOI：10.1073/pnas.1109434108

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 the segenes, 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 amore 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.

• 出版日期2011-12-27