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Sun Z, et al.  (2011) Molecular Determinants and Genetic Modifiers of Aggregation and Toxicity for the ALS Disease Protein FUS/TLS. PLoS Biol 9(4):e1000614

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

Status: Published Type: Journal Article PubMed ID: 21541367

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ALF1 ATP5 BUD26 CBT1 CDC4 CGI121 CLB2 COA4 COX5A CST6
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Cross-species Expression yg ball
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Topics Genes linked to topics (#11 - 20 )
CUE2 EAF1 ECM32 EDC3 FHL1 FMP48 FUM1 FYV7 FZO1 GCN4
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GIS2 HIT1 HMO1 HOF1 INM1 IPK1 IRC3 KGD2 LSM7 LTV1
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Topics Genes linked to topics (#31 - 40 )
MAK32 MFT1 MRP13 MRP49 MRPL39 MRT4 MSS1 MTC6 NAB3 NAM8
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Topics Genes linked to topics (#41 - 50 )
NOP16 NPR2 NSR1 NUP84 OCA1 PAB1 PET111 PIG1 PPM1 PUB1
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Topics Genes linked to topics (#51 - 60 )
RAD50 REC102 RIM15 RPL14A RPL19B RPP2B RPS10A RPS6B RPS8A RTT103
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Topics Genes linked to topics (#61 - 70 )
SBP1 SEY1 SKO1 SLM3 SLT2 SSE1 SYN8 TBS1 THP2 TIF2
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Topics Genes linked to topics (#71 - 80 )
TIF3 TIS11 TPS3 TRM11 TRM5 TSR2 VFA1 VHR1 VMS1 VPS64
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Topics Genes linked to topics (#81 - 90 )
YDL032W YDR248C YDR417C YGL072C YGL088W YGL165C YMR166C YNR005C YOR062C YOR309C
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Topics Genes linked to topics (#91 - 92 )
YPR147C ZDS2
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