Couthouis, J., Hart, M.P., Shorter, J., Dejesus-Hernandez, M., Erion, R., Oristano, R., Liu, A.X., Ramos, D., Jethava, N., Hosangadi, D., Epstein, J., Chiang, A., Diaz, Z., Nakaya, T., Ibrahim, F., Kim, H.J., Solski, J.A., Williams, K.L., Mojsilovic-Petrovic, J., Ingre, C., Boylan, K., Graff-Radford, N.R., Dickson, D.W., Clay-Falcone, D., Elman, L., McCluskey, L., Greene, R., Kalb, R.G., Lee, V.M., Trojanowski, J.Q., Ludolph, A., Robberecht, W., Andersen, P.M., Nicholson, G.A., Blair, I.P., King, O.D., Bonini, N.M., Van Deerlin, V., Rademakers, R., Mourelatos, Z., Gitler, A.D. (2011). Feature Article: From the Cover: A yeast functional screen predicts new candidate ALS disease genes.  Proc. Natl. Acad. Sci. U.S.A. 108(52): 20881--20890.

FBrf0217025

Research paper

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.

PMC3248518 (PMC) (EuropePMC)