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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Project:

Project ID:PR001934
Project DOI:doi: 10.21228/M8QT5K
Project Title:Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes
Project Summary:The 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 Name:Davide
First Name:Trotti
Address:900 Walnut Street, Philadelphia, PA 19107, USA
Email:davide.trotti@jefferson.edu
Phone:215-955-8416

Subject:

Subject ID:SU003234
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090

Factors:

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

mb_sample_id local_sample_id Sample source Genotype Treatment
SA338015C92DG_56Brain C9orf72 2DG
SA338016C92DG_07Brain C9orf72 2DG
SA338017C92DG_45Brain C9orf72 2DG
SA338018C92DG_47Brain C9orf72 2DG
SA338019C92DG_26Brain C9orf72 2DG
SA338020C92DG_30Brain C9orf72 2DG
SA338021C92DG_34Brain C9orf72 2DG
SA338022C9S_57Brain C9orf72 Saline
SA338023C9S_69Brain C9orf72 Saline
SA338024C9S_50Brain C9orf72 Saline
SA338025C9S_43Brain C9orf72 Saline
SA338026C9S_33Brain C9orf72 Saline
SA338027C9S_11Brain C9orf72 Saline
SA338028C9S_29Brain C9orf72 Saline
SA338029WTS_59Brain WT Saline
SA338030WTS_58Brain WT Saline
SA338031WTS_51Brain WT Saline
SA338032WTS_31Brain WT Saline
SA338033WTS_39Brain WT Saline
SA338034WTS_53Brain WT Saline
Showing results 1 to 20 of 20

Collection:

Collection ID:CO003227
Collection Summary:Animals were euthanized by CO2 inhalation 16 hours following the final injection and transcardially perfused with ice-cold PBS. Whole brains and spinal cords were then excised, flash frozen in liquid N2, and stored at –80°C
Sample Type:Brain cortex

Treatment:

Treatment ID:TR003243
Treatment Summary:Animals were administered i.p. injections of saline or 4 g/kg 2DG twice weekly for six weeks

Sample Preparation:

Sampleprep ID:SP003241
Sampleprep Summary:Metabolites from equal amounts of frontal cortex tissue were rapidly extracted in 80% ice-cold methanol. Extracted samples were vortexed twice, cleared by centrifugation at 14,000 x g for 20 minutes at 4°C, and stored at -80°C.

Combined analysis:

Analysis ID AN005111
Analysis type MS
Chromatography type HILIC
Chromatography system Thermo Vanquish
Column Merck SeQuant ZIC-pHILIC (150 x 2.1mm,5um)
MS Type ESI
MS instrument type Orbitrap
MS instrument name Thermo Q Exactive Orbitrap
Ion Mode UNSPECIFIED
Units peak intensity

Chromatography:

Chromatography ID:CH003867
Instrument Name:Thermo Vanquish
Column Name:Merck SeQuant ZIC-pHILIC (150 x 2.1mm,5um)
Column Temperature:30
Flow Gradient:85% to 30% A in 20 min followed by a wash with 30% A and re-equilibration at 85% A
Flow Rate:150 μL/min
Solvent A:100% acetonitrile
Solvent B:100% water; 0.1% ammonium hydroxide; 20 mM ammonium acetate
Chromatography Type:HILIC

MS:

MS ID:MS004848
Analysis ID:AN005111
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:A Sequant ZIC-pHILIC column (2.1 mm i.d. × 150 mm, particle size of 5 µm, Millipore Sigma) was used for separation of metabolites. A 2.1 × 20 mm guard column with the same packing material was used for protection of the analytical column. Flow rate was set at 150 μL/min. Buffers consisted of 100% acetonitrile for mobile phase A, and 0.1% NH4OH/20 mM CH3COONH4 in water for mobile phase B. The chromatographic gradient ran from 85% to 30% A in 20 min followed by a wash with 30% A and re-equilibration at 85% A. Column temperature was 30 C.
Ion Mode:UNSPECIFIED
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