Molecular Determinants and Genetic Modifiers of Aggregation and Toxicity for the ALS Disease Protein FUS/TLS

• DOI: 10.1371/journal.pbio.1000614
• Publication Date: 2011-04-26T20:31:52Z
• Authors: Zhihui Sun; Zamia Diaz; Xiaodong Fang; Michael P. Hart; Alessandra Chesi; James Shorter; Aaron D. Gitler
• Keywords: Stress granule; Frontotemporal lobar degeneration; Cytoplasmic inclusion; C9ORF72; Inclusion bodies

TDP-43 and FUS are RNA-binding proteins that form cytoplasmic inclusions in some forms of amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). Moreover, mutations linked to ALS FTLD. However, it is unknown whether aggregate cause toxicity by similar mechanisms. Here, we exploit a yeast model purified elucidate mechanisms aggregation toxicity. Like TDP-43, must the cytoplasm bind RNA confer yeast. These aggregates partition stress granule compartments just as they do patients. Importantly, isolation, spontaneously pore-like oligomers filamentous structures reminiscent requires prion-like domain, but unlike additional determinants within RGG domain critical for In further distinction ALS-linked not promote aggregation. Finally, genome-wide screens uncovered assembly metabolism genes modify Our findings suggest FUS, though proteins, disease phenotypes via distinct differences will likely have important therapeutic implications.