Dysfunction of the Cholesterol Biosynthetic Pathway in Huntington's Disease

Abstract

The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington's disease (HD), a dominantly inherited neurodegenerative disease. We show that the activity of the cholesterol biosynthetic pathway is altered in HD. In particular, the transcription of key genes of the cholesterol biosynthetic pathway is severely affected in vivo in brain tissue from HD mice and in human postmortem striatal and cortical tissue; this molecular dysfunction is biologically relevant because cholesterol biosynthesis is reduced in cultured human HD cells, and total cholesterol mass is significantly decreased in the CNS of HD mice and in brain-derived ST14A cells in which the expression of mutant huntingtin has been turned on. The transcription of the genes of the cholesterol biosynthetic pathway is regulated via the activity of sterol regulatory element-binding proteins (SREBPs), and we found an ϳ50% reduction in the amount of the active nuclear form of SREBP in HD cells and mouse brain tissue. As a consequence, mutant huntingtin reduces the transactivation of an SRE-luciferase construct even under conditions of SREBP overexpression or in the presence of an exogenous N-terminal active form of SREBP. Finally, the addition of exogenous cholesterol to striatal neurons expressing mutant huntingtin prevents their death in a dosedependent manner. We conclude that the cholesterol biosynthetic pathway is impaired in HD cells, mice, and human subjects, and that the search for HD therapies should also consider cholesterol levels as both a potential target and disease biomarker.

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

“…Previous studies reported that SREBP activity and its nuclear translocation were reduced in an inducible cell model of HD and in R6/2 brains. 7 Reduced nuclear levels of the N-terminal active fragment of SREBP2 (Nt-BP2) were also found in R6/2 astrocytes compared with wt astrocytes (Supplementary Figure 5a) and mRNA levels of SREBP2, but not of SREBP1, were decreased in HD NS-derived astrocytes compared with controls (Supplementary Figure 5b). Notably, a SRE sequence is present in the promoter region of SREBP2, 24 suggesting that reduced SREBP2 activation may in turn affect srebp2 gene expression.…”

“…Similar results were obtained with four other independent differentiations. (j) Neurite outgrowth quantification in Q140/7 neurons under glial-free conditions (vehicle) or in the presence of increasing doses of cholesterol (3,5,7,10,12, and 20 μg/ml) immunostained for MAP2. The graph shows the mean (a.u.)…”

“…[43][44][45] SREBP1 and SREBP2 activities are reduced in the presence of mutant HTT, both in vitro and in vivo. 7 Although the details of the underlying molecular mechanism are unknown, mutant HTT likely interferes with the Golgi-tonucleus translocation of the active SREBP. 7 The effects on neurite outgrowth in HD neurons following the silencing or overexpression of active SREBP2 in astrocytes demonstrate a link between cholesterol synthesis in astrocytes and subsequent efflux likely under the regulating effect of oxysterols, such as 24OHC.…”

“…3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC).…”

“…7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC). 9,10 However, it remains unclear how reduced brain cholesterol would become pathological for HD neurons.…”