Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington's disease

被引:88
作者
Valenza, M. [1 ,2 ]
Marullo, M. [1 ,2 ]
Di Paolo, E. [1 ,2 ]
Cesana, E. [3 ]
Zuccato, C. [1 ,2 ]
Biella, G. [3 ]
Cattaneo, E. [1 ,2 ]
机构
[1] Univ Milan, Dept Biosci, I-20133 Milan, Italy
[2] Univ Milan, Ctr Stem Cell Res, I-20133 Milan, Italy
[3] Univ Pavia, Dept Biol & Biotechnol, I-27100 Pavia, Italy
关键词
CENTRAL-NERVOUS-SYSTEM; GLIAL-CELLS; MUTANT HUNTINGTIN; MOUSE MODEL; PLASMA; 24S-HYDROXYCHOLESTEROL; BIOSYNTHESIS PATHWAY; EXPRESSION; DYSFUNCTION; METABOLISM; MANIFEST;
D O I
10.1038/cdd.2014.162
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyte-neuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD.
引用
收藏
页码:690 / 702
页数:13
相关论文
共 62 条
[1]   Apolipoprotein E protects against NMDA excitotoxicity [J].
Aono, M ;
Lee, Y ;
Grant, ER ;
Zivin, RA ;
Pearlstein, RD ;
Warner, DS ;
Bennett, ER ;
Laskowitz, DT .
NEUROBIOLOGY OF DISEASE, 2002, 11 (01) :214-220
[2]   Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology [J].
Ballas, Nurit ;
Lioy, Daniel T. ;
Grunseich, Christopher ;
Mandel, Gail .
NATURE NEUROSCIENCE, 2009, 12 (03) :311-317
[3]   Do oxysterols control cholesterol homeostasis? [J].
Björkhem, I .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 110 (06) :725-730
[4]   Mutant Huntingtin in Glial Cells Exacerbates Neurological Symptoms of Huntington Disease Mice [J].
Bradford, Jennifer ;
Shin, Ji-Yeon ;
Roberts, Meredith ;
Wang, Chuan-En ;
Sheng, Guoqing ;
Li, Shihua ;
Li, Xiao-Jiang .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (14) :10653-10661
[5]   Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms [J].
Bradford, Jennifer ;
Shin, Ji-Yeon ;
Roberts, Meredith ;
Wang, Chuan-En ;
Li, Xiao-Jiang ;
Li, Shihua .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (52) :22480-22485
[6]   Glial Cells Promote Dendrite Formation and the Reception of Synaptic Input in Purkinje Cells from Postnatal Mice [J].
Buard, Isabelle ;
Steinmetz, Celine C. ;
Claudepierre, Thomas ;
Pfrieger, Frank W. .
GLIA, 2010, 58 (05) :538-545
[7]   High-fat diet ameliorates neurological deficits caused by defective astrocyte lipid metabolism [J].
Camargo, Nutabi ;
Brouwers, Jos F. ;
Loos, Maarten ;
Gutmann, David H. ;
Smit, August B. ;
Verheijen, Mark H. G. .
FASEB JOURNAL, 2012, 26 (10) :4302-4315
[8]   SREBPs: SREBP function in glia-neuron interactions [J].
Camargo, Nutabi ;
Smit, August B. ;
Verheijen, Mark H. G. .
FEBS JOURNAL, 2009, 276 (03) :628-636
[9]   Liver X receptors, nervous system, and lipid metabolism [J].
Cermenati, G. ;
Brioschi, E. ;
Abbiati, F. ;
Melcangi, R. C. ;
Caruso, D. ;
Mitro, N. .
JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION, 2013, 36 (06) :435-443
[10]   Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis [J].
Christopherson, KS ;
Ullian, EM ;
Stokes, CCA ;
Mullowney, CE ;
Hell, JW ;
Agah, A ;
Lawler, J ;
Mosher, DF ;
Bornstein, P ;
Barres, BA .
CELL, 2005, 120 (03) :421-433