PXD038900

PXD038900 is an original dataset announced via ProteomeXchange.

Title	Repeat length of the C9orf72-associated glycine-alanine polypeptides affects their toxicity
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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:05:13.794.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ilian Atanassov
SpeciesList	scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: 7227;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-19 02:57:01	ID requested
1	2023-09-12 01:47:34	announced
⏵ 2	2023-11-14 09:05:14	announced	2023-11-14: Updated project metadata.

Mor, ó, n-Oset J, Fischer LKS, Jaur, é N, Zhang P, Jahn AJ, Sup, è, r T, Pahl A, Isaacs AM, Gr, ö, nke S, Partridge L, Repeat length of C9orf72-associated glycine-alanine polypeptides affects their toxicity. Acta Neuropathol Commun, 11(1):140(2023) [pubmed]

submitter keyword: Toxicity, Repeat Length, Drosophila,C9orf72, Glycine-Alanine

Linda Partridge
contact affiliation	Max Planck Institute for Biology of Ageing Joseph-Stelzmann-Str. 9b 50931 Cologne, Germany
contact email	partridge@age.mpg.de
lab head
Ilian Atanassov
contact affiliation	Max Planck Institute for Biology of Aging
contact email	Ilian.Atanassov@age.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038900
     1. Label: PRIDE project
     2. Name: Repeat length of the C9orf72-associated glycine-alanine polypeptides affects their toxicity