Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis Article Swipe
Rosana-Bristena Ionescu
,
Alexandra M. Nicaise
,
Julie A. Reisz
,
Eleanor C Williams
,
Pranathi Prasad
,
Cory M. Willis
,
Madalena B C Simões-Abade
,
Linda Sbarro
,
Monika Dzieciątkowska
,
Daniel Stephenson
,
Marta Suarez Cubero
,
Sandra Rizzi
,
Liviu Pirvan
,
Luca Peruzzotti‐Jametti
,
Valentina Fossati
,
Frank Edenhofer
,
Tommaso Leonardi
,
Christian Frezza
,
Irina Mohorianu
,
Angelo D’Alessandro
,
Stefano Pluchino
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1016/j.stem.2024.09.014
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1016/j.stem.2024.09.014
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 lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1016/j.stem.2024.09.014
- OA Status
- hybrid
- Cited By
- 16
- References
- 97
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4403586211
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4403586211Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1016/j.stem.2024.09.014Digital Object Identifier
- Title
-
Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosisWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-10-21Full publication date if available
- Authors
-
Rosana-Bristena Ionescu, Alexandra M. Nicaise, Julie A. Reisz, Eleanor C Williams, Pranathi Prasad, Cory M. Willis, Madalena B C Simões-Abade, Linda Sbarro, Monika Dzieciątkowska, Daniel Stephenson, Marta Suarez Cubero, Sandra Rizzi, Liviu Pirvan, Luca Peruzzotti‐Jametti, Valentina Fossati, Frank Edenhofer, Tommaso Leonardi, Christian Frezza, Irina Mohorianu, Angelo D’Alessandro, Stefano PluchinoList of authors in order
- Landing page
-
https://doi.org/10.1016/j.stem.2024.09.014Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
hybridOpen access status per OpenAlex
- OA URL
-
https://doi.org/10.1016/j.stem.2024.09.014Direct OA link when available
- Concepts
-
Biology, Multiple sclerosis, Neurotoxicity, Stem cell, Cell biology, Neuroscience, Cholesterol, Neural stem cell, Cell, Cancer research, Bioinformatics, Pharmacology, Computational biology, Immunology, Internal medicine, Endocrinology, Biochemistry, Toxicity, MedicineTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
16Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 14, 2024: 2Per-year citation counts (last 5 years)
- References (count)
-
97Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| sustainable_development_goals[0].id | https://metadata.un.org/sdg/2 |
| sustainable_development_goals[0].score | 0.5400000214576721 |
| sustainable_development_goals[0].display_name | Zero hunger |
| citation_normalized_percentile.value | 0.98477449 |
| citation_normalized_percentile.is_in_top_1_percent | True |
| citation_normalized_percentile.is_in_top_10_percent | True |