Journal Title
Title of Journal: Mol Neurobiol
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Abbravation: Molecular Neurobiology
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Authors: Miguel Moutinho Maria João Nunes Anita Q Gomes Maria João Gama Angel CedazoMinguez Cecília M P Rodrigues Ingemar Björkhem Elsa Rodrigues
Publish Date: 2014/08/02
Volume: 51, Issue: 3, Pages: 1489-1503
Abstract
The neuronalspecific cholesterol 24Shydroxylase CYP46A1 is important for brain cholesterol elimination Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal longterm potentiation suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway Conversely transgenic mice overexpressing CYP46A1 show an improved cognitive function These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function namely of isoprenylated small guanosine triphosphatebinding proteins sGTPases Our results show that CYP46A1 overexpression in SHSY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3hydroxy3methylglutarylCoA reductase activity and to an overall increase in membrane levels of RhoA Rac1 Cdc42 and Rab8 This increase is accompanied by a specific increase in RhoA activation Interestingly treatment with lovastatin or a geranylgeranyltransferaseI inhibitor abolished the CYP46A1 effect The CYP46A1mediated increase in sGTPases membrane abundance was confirmed in vivo in membrane fractions obtained from transgenic mice overexpressing this enzyme Moreover CYP46A1 overexpression leads to a decrease in the liver X receptor LXR transcriptional activity and in the mRNA levels of ATPbinding cassette transporter 1 subfamily A member 1 and apolipoprotein E This effect was abolished by inhibition of prenylation or by cotransfection of a RhoA dominantnegative mutant Our results suggest a novel regulatory axis in neurons under conditions of membrane cholesterol reduction by increased CYP46A1 expression neurons increase isoprenoid synthesis and sGTPase prenylation This leads to a reduction in LXR activity and consequently to a decrease in the expression of LXR target genesWe deeply thank Dr Peter Tontonoz Howard Hughes Medical Institute University of California Los Angeles USA for kindly providing the LXRE and LXRE mutABCA1 luciferase reporter plasmids and to Dr Peter Jordan Instituto Nacional de Saúde Doutor Ricardo Jorge Lisbon Portugal for the plasmid encoding a dominant negative mutant of RhoA pEGFP RhoA N19 This work was supported by FEDER COMPETE Programme and by national funds ER FCT—Fundação para a Ciência e a Tecnologia—project PTDC/SAUNMC/110809/2009 and PhD grants SFRH/BD/41848/2007 to MJN and SFRH/BD/78041/2011 to MM and by the Swedish Science Council and Swedish Brain Power IB
Keywords:
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