Modulation of the Isoprenoid/Cholesterol Biosynthetic Pathway During Neuronal Differentiation In Vitro
Open accessAbstract
During differentiation, neurons acquire their typical shape and functional properties. At present, it is unclear, whether this important developmental step involves metabolic changes. Here, we studied the contribution of the mevalonate (MVA) pathway to neuronal differentiation using the mouse neuroblastoma cell line N1E‐115 as experimental model. Our results show that during differentiation, the activity of 3‐hydroxy 3‐methylglutaryl Coenzyme A reductase (HMGR), a key enzyme of MVA pathway, and the level of Low Density Lipoprotein receptor (LDLr) decrease, whereas the level of LDLr‐related protein‐1 (LRP1) and the dimerization of Scavanger Receptor B1 (SRB‐1) rise. Pharmacologic inhibition of HMGR by simvastatin accelerated neuronal differentiation by modulating geranylated proteins. Collectively, our data suggest that during neuronal differentiation, the activity of the MVA pathway decreases and we postulate that any interference with this process impacts neuronal morphology and function. Therefore, the MVA pathway appears as an attractive pharmacological target to modulate neurological and metabolic symptoms of developmental neuropathologies. J. Cell. Biochem. 117: 2036–2044, 2016. © 2016 Wiley Periodicals, Inc.
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These changes suggest that low intracellular cholesterol content, as a consequence of HMGCR activity suppression in RTT fibroblasts, induces the classic feedback mechanism with activation of SREBP2 and the increase of its transcriptional targets such as LDLR and HMGCR.
“These changes suggest that low intracellular cholesterol content, as a consequence of HMGCR activity suppression in RTT fibroblasts, induces the classic feedback mechanism with activation of SREBP2 and the increase of its transcriptional targets such as LDLR (LDL receptor) and HMGCR [23,55,103,104,105,106,107].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [104]
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Experimental — accuracy not yet measuredHMGCR inhibition, and in turn the reduction in RhoA activation, are deeply involved in neurite outgrowth.
“For instance, we have previously demonstrated that HMGCR inhibition, and in turn the reduction in RhoA activation, are deeply involved in neurite outgrowth [10].”
From Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome (2022) · cites this paper as [10]
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Cholesterol metabolism in neurons and astrocytes
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Self-citationCholesterol in brain disease: Sometimes determinant and frequently implicated
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Self-citationKanekiyo, T., & Bu, G. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00093 · Cited by 281 · see citing works
A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome
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Segatto, M., Trapani, L., Di Tunno, I., Sticozzi, C., Valacchi, G., Hayek, J., & Pallottini, V. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104834 · Cited by 80 · see citing works
Self-citationSegatto, M., Leboffe, L., Trapani, L., & Pallottini, V. (2014) · Current Medicinal Chemistry · doi:10.2174/0929867321666140303142902 · Cited by 65 · see citing works
Self-citationSegatto, M., Manduca, A., Lecis, C., Rosso, P., Jozwiak, A., Swiezewska, E., Moreno, S., Trezza, V., & Pallottini, V. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2013.284 · Cited by 51 · see citing works
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Can Cholesterol Metabolism Modulation Affect Brain Function and Behavior?
Cartocci, V., Servadio, M., Trezza, V., & Pallottini, V. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25488 · Cited by 77 · see citing works
Self-citationSegatto, M., Tonini, C., Pfrieger, F. W., Trezza, V., & Pallottini, V. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133317 · Cited by 51 · see citing works
Self-citationBrain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome
Parente, M., Tonini, C., Buzzelli, V., Carbone, E., Trezza, V., & Pallottini, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063408 · Cited by 11 · see citing works
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- Authors
- Cartocci, V., Segatto, M., Di Tunno, I., Leone, S., Pfrieger, F. W., & Pallottini, V.
- Affiliations
- Roma Tre University (IT)
- University of Milan (IT)
- Department of Science Biomedical and Technology Science Section University Roma Tre Viale Marconi, 446, 00146 Rome Italy
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Pallottini, Valentina
- Venue
- Journal of Cellular Biochemistry
- Publisher
- Wiley
- Published
- 2016-02-05
- Volume
- 117
- Issue
- 9
- Pages
- 2036-2044
- ISSN
- 0730-2312 (ISSN-L)
- 1097-4644
- OpenAlex
- W2497792954
- Cited by
- 28
- References
- 7
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 6 · 2021: 2 · 2020: 6 · 2019: 6 · 2018: 2 · 2017: 2 · 2016: 1
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Iris (Roma Tre University) (submittedVersion)
- Funders
- University of “Roma Tre” (CLA 2013-2015)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- neuronal differentiation, mevalonate pathway, isoprenoid biosynthesis, cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-CoA reductase, simvastatin, LDL receptor, scavenger receptor class B type I, N1E-115 neuroblastoma cells, neurodevelopmental disorders
- MeSH terms
- Animals, Cell Differentiation, Cholesterol, Neurons, Receptors, LDL, Terpenes, Simvastatin, Tumor Suppressor Proteins, Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent, Low Density Lipoprotein Receptor-Related Protein-1, Cell Line, Tumor, Scavenger Receptors, Class B, Mice
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