Details

Autor(en) / Beteiligte

• Ju, Shulin
• Tardiff, Daniel F
• Han, Haesun
• Divya, Kanneganti
• Zhong, Quan
• Maquat, Lynne E
• Bosco, Daryl A
• Hayward, Lawrence J
• Brown, Jr, Robert H
• Lindquist, Susan
• Ringe, Dagmar
• Petsko, Gregory A
• Weissman, Jonathan S.

Titel

A yeast model of FUS/TLS-dependent cytotoxicity

Ist Teil von

• PLoS biology, 2011-04, Vol.9 (4), p.e1001052-e1001052

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2011

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• FUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression.