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Partial depletion of SRSF1 rescued the C9ORF72-repeat neurodegeneration-associated locomotor deficits in G4C2x36 Drosophila lines

ABSTRACT: In this study we investigated the role of SRSF1 in mitigating locomotor defect in C9ORF72-ALS/FTD Drosophila lines. We analysed the transcriptomes of Drosophila heads from the same lines: (i) control flies expressing 3 G4C2 repeats and a luciferase-RNAi control (G4C2x3 + C-RNAi); (ii) C9ORF72-ALS/FTD model expressing 36 G4C2 repeats and the RNAi control (G4C2x36 + C-RNAi); (iii) C9ORF72-ALS/FTD-neuroprotected flies expressing 36 G4C2 repeats and the disrupted SRSF1 allele (G4C2x36 + ΔSRSF1). RNA samples were profiled using Drosophila 3' IVT gene expression Affymetrix microarrays prior to qRT-PCR validation of the SRSF1 depletion in neuroprotected flies. This study is part of a larger study that investigates the mitigating role of SRSF1 at whole-genome level to detect transcriptomal alterations and neuronal hyperexcitability in C9ORF72-linked amyotrophic lateral sclerosis.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE138592 | GEO | 2021/07/21

REPOSITORIES: GEO

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Project description:G4C2 hexanucleotide repeat expansions in a non-coding region of the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). G4C2 insertion length is variable, and patients can carry up to several thousand repeats. Dipeptide repeat proteins (DPR) translated from G4C2 transcripts are thought to be a main driver of toxicity. Experiments in model organisms with relatively short DPR have shown that arginine-rich DPR are most toxic, while polyGlycine-Alanine (GA) DPRs cause only mild toxicity. However, GA is the most abundant DPR in patient brains, and experimental work in animals has generally relied on the use of low numbers of repeats, with DPRs often tagged for in vivo tracking. Whether repeat length, or tagging, affect the toxicity of GA has not been systematically assessed. Therefore, we generated Drosophila fly lines expressing GA100, GA200 or GA400 specifically in adult neurons. Consistent with previous studies, expression of GA100 and GA200 caused only mild toxicity. In contrast, neuronal expression of GA400 drastically reduced climbing ability and survival of the flies, indicating that long GA DPRs can be highly toxic in vivo. This toxicity could be abolished by tagging GA400. Proteomics analysis of fly brains showed a repeat-length-dependent modulation of the brain proteome, with GA400 causing earlier and stronger changes than shorter GA proteins. PolyGA expression up-regulated proteins involved in ER to Golgi trafficking, and down-regulated proteins involved in insulin signalling. Experimental down-regulation of Tango1, a highly conserved regulator of ER-to Golgi transport, partially rescued GA400 toxicity, suggesting that misregulation of this process contributes to polyGA toxicity. Experimentally increasing insulin signaling also rescued GA toxicity. In summary, our data show that long polyGA proteins can be highly toxic in vivo, and that they may therefore contribute to ALS/FTD pathogenesis in humans patients.

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Partial depletion of SRSF1 rescued the C9ORF72-repeat neurodegeneration-associated locomotor deficits in G4C2x36 Drosophila lines

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