Dissecting the roles of EIF4G homologs reveals DAP5 as a modifier of CGG repeat-associated toxicity in a Drosophila model of FXTAS

Neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a CGG trinucleotide repeat expansion in the 5′ UTR of FMR1. Expanded CGG repeat RNAs form stable secondary structures, which in turn support repeat-associated non-AUG (RAN) translation to produce toxic peptides. Th...

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Published in:	Neurobiology of disease Vol. 184; p. 106212
Main Authors:	Malik, Indranil, Tseng, Yi-Ju, Wieland, Clare M., Green, Katelyn M., Zheng, Kristina, Calleja, Katyanne, Todd, Peter K.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-08-2023 Elsevier
Subjects:	Animals Ataxia - genetics DAP5 Drosophila - metabolism Drosophila melanogaster - metabolism Drosophila Proteins - genetics Drosophila Proteins - metabolism Eukaryotic Initiation Factor-4G - genetics Fragile X Fragile X Mental Retardation Protein - genetics Fragile X Mental Retardation Protein - metabolism Fragile X Syndrome - genetics FXTAS Mammals - metabolism RAN translation repeat expansion disorders Tremor - genetics Trinucleotide Repeat Expansion RAN translation repeat expansion disorders DAP5 Fragile X FXTAS
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Summary:	Neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a CGG trinucleotide repeat expansion in the 5′ UTR of FMR1. Expanded CGG repeat RNAs form stable secondary structures, which in turn support repeat-associated non-AUG (RAN) translation to produce toxic peptides. The parameters that impact RAN translation initiation efficiency are not well understood. Here we used a Drosophila melanogaster model of FXTAS to evaluate the role of the eIF4G family of eukaryotic translation initiation factors (EIF4G1, EIF4GII and EIF4G2/DAP5) in modulating RAN translation and CGG repeat-associated toxicity. DAP5 knockdown robustly suppressed CGG repeat-associated toxicity and inhibited RAN translation. Furthermore, knockdown of initiation factors that preferentially associate with DAP5 (such as EIF2β, EIF3F and EIF3G) also selectively suppressed CGG repeat-induced eye degeneration. In mammalian cellular reporter assays, DAP5 knockdown exhibited modest and cell-type specific effects on RAN translation. Taken together, these data support a role for DAP5 in CGG repeat associated toxicity possibly through modulation of RAN translation. •CGG repeat associated non-AUG (RAN) translation generates neurotoxic peptides.•DAP5 is a non-canonical initiation factor which shares homology with eIF4G1.•Loss of NAT1, the fly homolog of DAP5, suppresses CGG repeat associated toxicity.•DAP5 expression modifies RAN translation of CGG repeats in flies and human cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author Contributions IM conceptualized the study with input from PKT. IM conducted most of the experiments with assistance from Y-JT on cell-based assays and microscopy, CW on mammalian neuronal experiments, and KMG, KZ, and KC on Drosophila studies. Data curation and Formal analysis was done by IM and PKT. IM and PKT acquired funding to support this project. IM and PKT wrote the original manuscript with editorial input from all authors.
ISSN:	0969-9961 1095-953X 1095-953X
DOI:	10.1016/j.nbd.2023.106212