Title: Cholesterol loss during glutamate-mediated excitotoxicity
Authors: Sodero, Alejandro O ×
Joris vriens, Joris
Ghosh, Debapriya
Stegner, David
Brachet, Anna
Pallotto, Marta
Sassoè-Pognetto, Marco
Brouwers, Jos F
Helms, J Bernd
Nieswandt, Bernhard
Voets, Thomas
Dotti, Carlos #
Issue Date: 17-Feb-2012
Publisher: Nature Publishing Group
Series Title: EMBO Journal vol:31 issue:7 pages:1764-73
Article number: 10.1038/emboj.2012.31
Abstract: The deregulation of brain cholesterol metabolism is typical in acute neuronal injury (such as stroke, brain trauma and epileptic seizures) and chronic neurodegenerative diseases (Alzheimer's disease). Since both conditions are characterized by excessive stimulation of glutamate receptors, we have here investigated to which extent excitatory neurotransmission plays a role in brain cholesterol homeostasis. We show that a short (30 min) stimulation of glutamatergic neurotransmission induces a small but significant loss of membrane cholesterol, which is paralleled by release to the extracellular milieu of the metabolite 24S-hydroxycholesterol. Consistent with a cause-effect relationship, knockdown of the enzyme cholesterol 24-hydroxylase (CYP46A1) prevented glutamate-mediated cholesterol loss. Functionally, the loss of cholesterol modulates the magnitude of the depolarization-evoked calcium response. Mechanistically, glutamate-induced cholesterol loss requires high levels of intracellular Ca(2+), a functional stromal interaction molecule 2 (STIM2) and mobilization of CYP46A1 towards the plasma membrane. This study underscores the key role of excitatory neurotransmission in the control of membrane lipid composition, and consequently in neuronal membrane organization and function.
ISSN: 0261-4189
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Development and Regeneration - miscellaneous (+)
Laboratory of Ion Channel Research
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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