Summary of project PR002811
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 PR002811. The data can be accessed directly via it's Project DOI: 10.21228/M89P0K This work is supported by NIH grant, U2C- DK119886. See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002811 |
| Project DOI: | doi: 10.21228/M89P0K |
| Project Title: | Lipidomics profiling of NMNAT2–SARM1 pathway modulation in mouse cortical neurodegeneration |
| Project Summary: | NAD⁺ homeostasis is vital for neuronal health, as demonstrated by the opposing roles of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), a NAD⁺-synthesizing enzyme, and sterile alpha and TIR motif-containing protein 1 (SARM1), a NAD⁺ hydrolase. Neurodegenerative insults that decrease NMNAT2 activate SARM1, leading to axon loss. To understand how the NMNAT2–SARM1 axis influences brain energy metabolism, we employed multi-omics approaches to investigate the metabolic changes resulting from neuronal NMNAT2 loss. Loss of NMNAT2 in glutamatergic neurons leads to a significant metabolic shift in the cerebral cortex from glucose to lipid catabolism, reduced lipid abundance, and pronounced neurodegenerative phenotypes and motor behavioral deficits. These metabolic disturbances are accompanied by altered glial expression of enzymes regulating glucose and lipid metabolism, enhanced inflammatory signaling, and disrupted astrocytic transcriptomic profiles related to cholesterol synthesis and immune activation. Notably, SARM1 deletion in NMNAT2-deficient mice restored lipid metabolism, astrocyte transcriptomic profiles, and mitigated neurodegeneration and motor behaviors. These findings suggest that neuronal NAD⁺ depletion triggers maladaptive, SARM1-dependent metabolic reprogramming, shifting energy use from glucose to lipids, which in turn promotes inflammation and neurodegeneration. Metabolomic profiling revealed decreased NAD⁺ and glycolytic intermediates, accumulation of fatty acid oxidation and ketone metabolites, and widespread depletion of cholesterol- and phospholipid-related species, all of which were normalized by SARM1 deletion. |
| Institute: | Indiana University Bloomington |
| Last Name: | Niou |
| First Name: | Zhen-Xian |
| Address: | 400 EAST SEVENTH STREET, BLOOMINGTON, IN, 47405, USA. |
| Email: | niouz@iu.edu |
| Phone: | 7022097321 |
Summary of all studies in project PR002811
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST004451 | Lipidomics profiling of NMNAT2–SARM1 pathway modulation in mouse cortical neurodegeneration | Mus musculus | Indiana University Bloomington | MS | 2026-01-06 | 1 | 25 | Uploaded data (32.4M)* |
