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Cholesterol reduction impairs exocytosis of synaptic vesicles
Open accessAbstract
Cholesterol and sphingolipids are abundant in neuronal membranes, where they help the organisation of the membrane microdomains involved in major roles such as axonal and dendritic growth, and synapse and spine stability. The aim of this study was to analyse their roles in presynaptic physiology. We first confirmed the presence of proteins of the exocytic machinery (SNARES and Ca(v)2.1 channels) in the lipid microdomains of cultured neurons, and then incubated the neurons with fumonisin B (an inhibitor of sphingolipid synthesis), or with mevastatin or zaragozic acid (two compounds that affect the synthesis of cholesterol by inhibiting HMG-CoA reductase or squalene synthase). The results demonstrate that fumonisin B and zaragozic acid efficiently decrease sphingolipid and cholesterol levels without greatly affecting the viability of neurons or the expression of synaptic proteins. Electron microscopy showed that the morphology and number of synaptic vesicles in the presynaptic boutons of cholesterol-depleted neurons were similar to those observed in control neurons. Zaragozic acid (but not fumonisin B) treatment impaired synaptic vesicle uptake of the lipophilic dye FM1-43 and an antibody directed against the luminal epitope of synaptotagmin-1, effects that depended on the reduction in cholesterol because they were reversed by cholesterol reloading. The time-lapse confocal imaging of neurons transfected with ecliptic SynaptopHluorin showed that cholesterol depletion affects the…
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“One mechanism that might contribute to these effects is the restoration of membrane lipid rafts, cholesterol-enriched microdomains that organize signaling molecules and synaptic proteins and are required for efficient synaptic transmission (Korinek et al., 2020;Linetti et al., 2010).”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Linetti et al., 2010
In the citing paper
“Cholesterol is essential for neurons, because a lack of cholesterol leads to synapse degeneration, impaired synaptic vesicle exocytosis and neurotransmission, and overall decreased neuronal activity.[42][43][44]”
From Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function (2024) · cites this paper as [43]
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“These findings also suggest that within the striatum, the astrocyte-neuron signaling may be synapse-and cell-specific by acting at least on the DRD2-MSNs, as recently proposed 53 .”
From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [53]
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Metadata
- Authors
- Linetti, A., Fratangeli, A., Taverna, E., Valnegri, P., Francolini, M., Cappello, V., Matteoli, M., Passafaro, M., & Rosa, P.
- Affiliations
- University of Milan (IT)
- Corresponding author
- Rosa, Patrizia
- ORCID
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2010-02-15
- Volume
- 123
- Issue
- 4
- Pages
- 595-605
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2160339294
- Cited by
- 209
- References
- 53
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 13 · 2023: 14 · 2022: 15 · 2021: 12 · 2020: 17 · 2019: 15 · 2018: 13 · 2017: 11 · 2016: 11 · 2015: 14 · 2014: 19 · 2013: 16 · 2012: 5
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- cc-by
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, cc-by)
- Funders
- Compagnia di San Paolo (2005.1964)
- Università degli Studi di Milano
- Fondazione Cariplo
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Consiglio Nazionale delle Ricerche
- Università degli Studi di Genova
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- cholesterol, sphingolipids, synaptic vesicle exocytosis, presynaptic terminals, lipid rafts, fumonisin B, zaragozic acid, mevastatin, HMG-CoA reductase inhibition, squalene synthase inhibition, SNARE proteins, synaptotagmin-1, cholesterol depletion
- MeSH terms
- Animals, Anticholesteremic Agents, Cells, Cultured, Cholesterol, Exocytosis, Immunoglobulin G, Lovastatin, Models, Neurological, Neurons, Sphingolipids, Synaptic Vesicles, Tricarboxylic Acids, Presynaptic Terminals, Bridged Bicyclo Compounds, Heterocyclic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Calcium Channels, N-Type, Membrane Microdomains, Fumonisins, Microscopy, Electron, Transmission, SNARE Proteins, Synaptotagmin I, Rats
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