Summary of Study ST003112

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001934. The data can be accessed directly via it's Project DOI: 10.21228/M8QT5K This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003112
Study TitleGlucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes
Study SummaryThe most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brains of asymptomatic C9-BAC mice. We found that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a potential mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and suggest a feedforward loop model that opens several opportunities for therapeutic intervention.
Institute
Thomas Jefferson University
Last NameTrotti
First NameDavide
Address900 Walnut Street, Philadelphia, PA 19107, USA
Emaildavide.trotti@jefferson.edu
Phone215-955-8416
Submit Date2024-02-29
Raw Data AvailableYes
Raw Data File Type(s)mzXML
Analysis Type DetailLC-MS
Release Date2024-03-29
Release Version1
Davide Trotti Davide Trotti
https://dx.doi.org/10.21228/M8QT5K
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Sample source
SA338015C92DG_56Brain | Genotype:C9orf72 | Treatment:2DG
SA338016C92DG_07Brain | Genotype:C9orf72 | Treatment:2DG
SA338017C92DG_45Brain | Genotype:C9orf72 | Treatment:2DG
SA338018C92DG_47Brain | Genotype:C9orf72 | Treatment:2DG
SA338019C92DG_26Brain | Genotype:C9orf72 | Treatment:2DG
SA338020C92DG_30Brain | Genotype:C9orf72 | Treatment:2DG
SA338021C92DG_34Brain | Genotype:C9orf72 | Treatment:2DG
SA338022C9S_57Brain | Genotype:C9orf72 | Treatment:Saline
SA338023C9S_69Brain | Genotype:C9orf72 | Treatment:Saline
SA338024C9S_50Brain | Genotype:C9orf72 | Treatment:Saline
SA338025C9S_43Brain | Genotype:C9orf72 | Treatment:Saline
SA338026C9S_33Brain | Genotype:C9orf72 | Treatment:Saline
SA338027C9S_11Brain | Genotype:C9orf72 | Treatment:Saline
SA338028C9S_29Brain | Genotype:C9orf72 | Treatment:Saline
SA338029WTS_59Brain | Genotype:WT | Treatment:Saline
SA338030WTS_58Brain | Genotype:WT | Treatment:Saline
SA338031WTS_51Brain | Genotype:WT | Treatment:Saline
SA338032WTS_31Brain | Genotype:WT | Treatment:Saline
SA338033WTS_39Brain | Genotype:WT | Treatment:Saline
SA338034WTS_53Brain | Genotype:WT | Treatment:Saline
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