Cholesterol loss during glutamate-mediated excitotoxicity.

Alejandro O Sodero, Joris Vriens, Debapriya Ghosh, David Stegner, Anna Brachet, Marta Pallotto, Marco Sassoè-Pognetto, Jos F Brouwers, J Bernd Helms, Bernhard Nieswandt, Thomas Voets, Carlos G Dotti
The EMBO Journal. 2012-02-17; 31(7): 1764-1773
DOI: 10.1038/emboj.2012.31

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1. EMBO J. 2012 Apr 4;31(7):1764-73. doi: 10.1038/emboj.2012.31. Epub 2012 Feb 17.

Cholesterol loss during glutamate-mediated excitotoxicity.

Sodero AO(1), Vriens J, Ghosh D, Stegner D, Brachet A, Pallotto M,
Sassoè-Pognetto M, Brouwers JF, Helms JB, Nieswandt B, Voets T, Dotti CG.

Author information:
(1)VIB Center for Biology of Disease, Katholieke Universiteit Leuven, Leuven,

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.

DOI: 10.1038/emboj.2012.31
PMCID: PMC3321209
PMID: 22343944 [Indexed for MEDLINE]

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