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Effects of overexpression of a C9orf72 repeat expansion linked to GFP, or a GFP control in human HEK293 cells, in the presence or absence of the EIF2B activator DNL343.

ABSTRACT: Neuronal TDP-43 aggregates are a hallmark ALS pathology. The integrated stress response (ISR) occurs downstream of TDP-43 pathology and may exacerbate TDP-43 aggregation and neurodegeneration. Here we assessed the effects of overexpression of a GFP-taggted C9orf72 repeat expansion in HEK293 cells on the transcriptome, in the presence or ascence of the EIF2B activiting small molecule DNL343. Expression of (G4C2)71-GFP upregulated most of the pre-defined ISR genes compared to GFP expression alone. These transcriptional changes were largely corrected by DNL343 treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281958 | GEO | 2025/06/30

REPOSITORIES: GEO

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Project description:Purpose: The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We performed RNA-seq analysis of cerebellum collected from mice harboring a homozygous point mutation in eIF2B5 (HO R191H), a mutation that causes a severe form of VWM in humans and compared gene expression to wildtype age-matched littermates to identify transcriptomic differences at early, mid and late time points during disease progression. We also performed RNA-seq on cerebellum collected from animals treated with the eIF2B activator 2BAct for 1 month to determine to what extent small molecule treatment could normalize the VWM transcriptome. Methods: Samples were collected at 2, 5, and 7 months of age. In addition, HO R191H and WT mice treated with and without with the eIF2B activator 2BAct for 1 month were profiled. RNA-seq libraries were prepared using purified RNA isolated from frozen tissue using the RNeasy Mini kit. RNA quality and concentration were assayed using a Fragment Analyzer instrument. RNA-seq libraries were prepared using the TruSeq Stranded Total RNA kit paired with the Ribo-Zero rRNA removal kit. Libraries were sequenced on an Illumina HiSeq 4000 instrument. For the experiment comparing different ages, N = 3 males/genotype/time point. For the 4-week 2BAct treatment experiment, N = 3 females/condition. Conclusions: HO R191H mutant brains show an elevated gene expression signature of the Integrated Stress Reponse in mice as early as 2 months, preceding the appearance of overt pathology in these animals. The expression of the ISR-related genes does not significantly increases at 5 months and 7 months of age. One month of treatment with 2BAct completely prevented the expression of ISR-related in genes in 2 month old animals.

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Effects of overexpression of a C9orf72 repeat expansion linked to GFP, or a GFP control in human HEK293 cells, in the presence or absence of the EIF2B activator DNL343.

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