Dissecting the Roles of EIF4G Homologs Reveals DAP5 As a Modifier of CGG Repeat-associated Toxicity in a Drosophila Model of FXTAS

Overview

Journal Neurobiol Dis

Specialty Neurology

Date 2023 Jun 23

PMID 37352983

Authors

Indranil Malik

Yi-Ju Tseng

Clare M Wieland

Katelyn M Green

Kristina Zheng

Katyanne Calleja

Peter K Todd

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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