Altered cholesterol homeostasis contributes to enhanced excitotoxicity in Huntington's disease.
Recent findings suggest that altered cholesterol homeostasis may contribute to the pathophysiology of Huntington's disease (HD). To understand the underlying mechanisms, here we used a combination of two-photon microscopy, epifluorescence, and biochemical methods to visualize and quantify lipid distribution in cell cultures expressing mutant huntingtin. Such expression promotes lipid imbalance, and cholesterol accumulation in cellular and murine models and in HD-affected human brains. Interestingly, cells expressing mutant huntingtin also showed higher content of ordered domains in their plasma membranes. These findings correlated with high levels of caveolin-1 and glycosphingolipid GM1, two well-defined markers of cholesterol-enriched domains, at the cell surface. In addition, cells expressing mutant huntingtin showed increased localization of NMDA receptors with cholesterol-enriched domains, contributing to increased NMDA receptor susceptibility to excitotoxic insults. Treatment with simvastatin or β-cyclodextrin, two cholesterol-lowering drugs, reduced the content of ordered domains at the cell surface, which in turn, protected cells against NMDA-mediated excitotoxicity. Taken together, our results indicate that mutant huntingtin produces accumulation of cholesterol and alters its cellular distribution that contributes to NMDA-mediated excitotoxicity. Administration of drugs that recover this effect, such as simvastatin could be beneficial for the treatment of HD.
del Toro
Daniel
D
Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
Xifró
Xavier
X
Pol
Albert
A
Humbert
Sandrine
S
Saudou
Frédéric
F
Canals
Josep M
JM
Alberch
Jordi
J
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001921:Brain / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D007202:Indicators and Reagents; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology*; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology
D000924:Anticholesteremic Agents; D051242:Caveolin 1; D018690:Excitatory Amino Acid Agonists; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007202:Indicators and Reagents; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014280:Triglycerides; D047392:beta-Cyclodextrins; D016202:N-Methylaspartate; D004247:DNA; D002784:Cholesterol; D019821:Simvastatin