Summary of project PR002070
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 PR002070. The data can be accessed directly via it's Project DOI: 10.21228/M81Z4C This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002070 |
| Project DOI: | doi: 10.21228/M81Z4C |
| Project Title: | Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis |
| Project Summary: | Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of cholesteryl ester-enriched lipid droplets. An HMG-CoA reductase-mediated lipogenic state was found to induce secretion of the SASP in PMS iNSC conditioned media via transcriptional regulation by cholesterol-dependent transcription factors. SASP from PMS iNSCs induced neurotoxicity. Chemical targeting of HMG-CoA reductase using the cholesterol-lowering drug simvastatin (SV) reprogrammed the SASP and rescued neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically. |
| Institute: | University of Colorado Denver |
| Laboratory: | Lab of Angelo D'Alessandro in collaboration with lab of Stefano Pluchino (Univ of Cambridge) |
| Last Name: | Haines |
| First Name: | Julie |
| Address: | 12801 E 17th Ave, Room 1303, Aurora, Colorado, 80045, USA |
| Email: | julie.haines@cuanschutz.edu |
| Phone: | 3037243339 |
Summary of all studies in project PR002070
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003328 | Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis - cellular lipidomics | Homo sapiens | University of Colorado Denver | MS | 2024-08-08 | 1 | 42 | Uploaded data (7.2G)* |
| ST003330 | Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis - media lipidomics | Homo sapiens | University of Colorado Denver | MS | 2024-08-08 | 1 | 24 | Uploaded data (643.2M)* |
| ST003331 | Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis - cellular metabolomics | Homo sapiens | University of Colorado Denver | MS | 2024-08-08 | 1 | 21 | Uploaded data (2.1G)* |
| ST003332 | Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis - media metabolomics | Homo sapiens | University of Colorado Denver | MS | 2024-08-08 | 1 | 24 | Uploaded data (1.7G)* |
