Summary of Study ST003118
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.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
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.
| Study ID | ST003118 |
| Study Title | Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes - Study 2 |
| Study 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 | Trotti |
| First Name | Davide |
| Address | 900 Walnut Street, Philadelphia, PA 19107, USA |
| davide.trotti@jefferson.edu | |
| Phone | 215-955-8416 |
| Submit Date | 2024-03-01 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | raw(Thermo) |
| Analysis Type Detail | LC-MS |
| Release Date | 2024-03-29 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
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: | SU003235 |
| 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 | Treatment |
|---|---|---|---|
| SA338035 | 2DG_1 | Brain | 2DG |
| SA338036 | 2DG_5 | Brain | 2DG |
| SA338037 | 2DG_4 | Brain | 2DG |
| SA338038 | 2DG_2 | Brain | 2DG |
| SA338039 | 2DG_3 | Brain | 2DG |
| SA338040 | Saline_5 | Brain | Saline |
| SA338041 | Saline_4 | Brain | Saline |
| SA338042 | Saline_1 | Brain | Saline |
| SA338043 | Saline_2 | Brain | Saline |
| SA338044 | Saline_3 | Brain | Saline |
| Showing results 1 to 10 of 10 |
Collection:
| Collection ID: | CO003228 |
| 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 for biochemical analysis. |
| Sample Type: | Brain |
Treatment:
| Treatment ID: | TR003244 |
| Treatment Summary: | Mice were administered i.p. injections of saline (vehicle) or 4 g/kg 2DG (Cayman Chemical) twice weekly for six weeks. |
Sample Preparation:
| Sampleprep ID: | SP003242 |
| 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 | AN005112 |
|---|---|
| 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: | CH003868 |
| 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: | MS004849 |
| Analysis ID: | AN005112 |
| Instrument Name: | Thermo Q Exactive Orbitrap |
| Instrument Type: | Orbitrap |
| MS Type: | ESI |
| MS Comments: | 1. 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 100% acetonitrile 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 |
