Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington's disease.
We have recently reported significantly reduced levels of the mRNA of genes critical for the cholesterol biosynthesis pathway in the brains of mice and patients with Huntington's disease (HD), which are indicative of a biological dysfunction. We here show that the brains of R6/2 transgenic mice have progressively decreasing levels of the cholesterol precursors, lathosterol and lanosterol, and declining 3-hydroxy-3-methylglutaryl coenzyme A reductase activity starting from pre-symptomatic stages. We also show that, despite the progressive reduction of brain cholesterol biosynthesis, steady-state levels of total cholesterol remain constant, thus suggesting that compensatory mechanisms are in operation. These in vivo findings indicate a consistent and progressive reduction in the activity of the cholesterol biosynthesis pathway in HD brain. The defect occurs early in these mice and generates lower levels of newly synthesized cholesterol and its intermediates, which may affect different aspects of the disease.
Valenza
Marta
M
Department of Pharmacological Sciences and Centre for Stem Cell Research, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Leoni
Valerio
V
Tarditi
Alessia
A
Mariotti
Caterina
C
Björkhem
Ingeman
I
Di Donato
Stefano
S
Cattaneo
Elena
E
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000032:analysis / Q000378:metabolism; D007810:Lanosterol / Q000032:analysis / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D007810:Lanosterol; C001521:lathosterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases