Getting a handle on Huntington's disease: the case for cholesterol

Bedside to Bench

Since the first description in 1872 (ref. 1) of Huntington's disease—a hereditary neurodegenerative disease characterized by progressive movement disorder, cognitive decline and psychiatric disturbances—tremendous efforts have been made to cure it. However, no effective therapy exists, except for a few symptomatic treatments, such as tetrabenezine, which attenuates involuntary movement.

A recent clinical study of people with Huntington's disease hints that low concentrations of brain cholesterol may contribute to disease and bolsters the emerging idea that targeting cholesterol metabolism has the potential to be beneficial². The findings dovetail with studies in animals and people suggesting that low amounts of brain cholesterol might play a part in a range of neurodegenerative disorders.

Huntington's disease is one of the devastating neurodegenerative disorders resulting from expansion of a genomic trinucleotide CAG repeat, which encodes a polyglutamine tract in causative proteins. Although the genes encoding these proteins are distinct from one another except for the expanded CAG repeats, polyglutamine-mediated neurodegenerative disorders share salient features, such as a selective loss of neurons within the central nervous system and a slow progression of neurological deficits.

Therefore, the pathophysiology of Huntington's disease is likely to be closely related to that of other polyglutamine diseases. In support of this view, various cell culture and animal studies show that the pathogenic polyglutamine proteins have a propensity to accumulate in neurons and, thereby, trigger several molecular events that lead to neuronal dysfunction and eventual cell death.

For example, it has been suggested that nuclear accumulation of huntingtin, the causative protein of Huntington's disease, impairs transcription by interfering with the activity of transcription factors³. It is, therefore, not surprising that the abnormal accumulation of pathogenic polyglutamine proteins is a major target of therapeutic interventions⁴. Mitochondrial dysfunction, axonal transport disruption and oxidative stress have also been implicated in the molecular mechanisms of polyglutamine diseases. Thus, the quantitative assessment of these cellular events is important for the development of therapy as well as for the evaluation of disease progression.

In a recent clinical study, Leoni et al.² showed that concentrations of 24S-hydroxycholesterol, a cholesterol metabolite produced in the brain, are substantially decreased in the plasma of people with Huntington's disease compared with healthy subjects. They found that this decrease in 24S-hydroxycholesterol parallels the decrease in volume of the caudate, a brain region affected in the disease, observed from before onset to early stages of Huntington's disease⁴.

24S-hydroxycholesterol helps maintain constant levels of brain cholesterol, which is required for proper neuronal activity. Brain cholesterol is metabolically separated from other pools by the blood-brain barrier. By virtue of this tight segregation, cholesterol metabolism within the brain is isolated from any changes in the circulating amounts of lipids that result from diet or medication. Brain cholesterol does not come from the blood but is synthesized locally, suggesting the need for elaborate cellular machinery to remove cholesterol from the brain to the circulation to maintain the steady-state level of brain cholesterol. This intrabrain metabolism of cholesterol is ensured by cholesterol 24- hydroxylase, a cytochrome P450 enzyme (encoded by CYP46A1) that catalyzes the conversion of cholesterol to 24S-hydroxycholesterol. Whereas unmodified cholesterol does not diffuse into the bloodstream, 24S-hydroxycholesterol crosses the blood-brain barrier.

The study by Leoni et al.² strongly indicates that the level of plasma 24S-hydroxycholesterol is a promising biomarker that reflects the early progression of neurodegeneration in the disease. Although there is a possibility that the decrease in 24S-hydroxycholesterol simply reflects the reduction in the number of metabolically healthy neurons within affected brain areas, a reasonable hypothesis is that the proper metabolism of cholesterol is impaired in the brains of people with Huntington's disease.

Other studies support this view. For instance, pathogenic huntingtin proteins have been shown to diminish brain cholesterol by inducing transcriptional downregulation of a series of sterol regulatory element–regulated gene products that are essential for cholesterol biosynthesis⁵. A decreased amount of 24S-hydroxycholesterol has also been reported in a transgenic mouse model of Huntington's disease⁶. These human and animal studies strongly underscore the need to exploit pharmacological correction of brain cholesterol metabolism as a promising therapeutic strategy against Huntington's disease.

Dysregulation of cholesterol could affect the nervous system in multiple ways. Cholesterol is an essential component of mammalian cellular membranes, being required for proper permeability and fluidity. Although the human brain represents only two percent of total body mass, it is the most cholesterol-rich organ in the body, accounting for approximately one-fourth of total body cholesterol. Brain cholesterol is not only a major component of myelin and cell membranes but also necessary for a number of normal brain functions, such as membrane trafficking, signal transduction, neurotransmitter release and synaptogenesis.

The tendrils of cholesterol metabolism are also far reaching. The process of synthesizing 24S-hydroxycholesterol generates nonsterol isoprenoids, geranylgeranyl pyrophosphate and farnesyl pyrophosphate, which activate small GTP-binding proteins such as Rho (Fig. 1). Given that Rho family GTPases control neuronal activities and survival through the regulation of neurite outgrowth, cellular polarity, axonal navigation and synapse formation, cholesterol 24-hydroxylase would seem to play an important part in the maintenance of brain functions. This hypothesis has been tested in the Cyp46a1-knockout mouse, which shows a learning defect owing to the decreased metabolism of brain cholesterol⁷. Moreover, geranylgeraniol, a precursor of geranylgeranyl pyrophosphate, improves hippocampal long-term potentiation in this mouse model⁷.

Figure 1: Disrupted cholesterol metabolism may contribute to neurodegeneration in Huntington's disease.

Katie Vicari

Cholesterol is synthesized from acetyl-CoA in adult brain. Brain-generated cholesterol does not cross the blood-brain barrier, but 24S-hydroxycholesterol, an oxygenated metabolite of cholesterol, is capable of diffusing into the bloodstream. The metabolism of brain cholesterol also generates nonsterol isoprenoids, which are required to activate the small GTP-binding proteins that regulate normal neuronal functions. Pathogenic huntingtin proteins inhibit the transcription of sterol regulatory element (SRE)-regulated gene products that are essential for cholesterol biosynthesis, resulting in a decreased concentration of plasma 24S-hydroxycholesterol—which has the potential to serve as a biomarker for disease progression².

Cholesterol dysregulation has also been reported in a variety of other neurodegenerative diseases including Alzheimer's disease, in which the plasma concentrations of 24S-hydroxycholesterol decrease as the disease progresses⁸. Amyloid-β oligomers, the causative proteins of Alzheimer's disease, have been shown to inhibit brain cholesterol synthesis⁹. Furthermore, an epidemiological study suggests an association between certain CYP46A1 polymorphisms and a higher risk of Alzheimer's disease¹⁰. It has also been documented that hypercholesterolemia protects against amyotrophic lateral sclerosis, an adult-onset motor neuron disease¹¹. Notably, mice lacking the liver X receptor-β, the receptor for 24S-hydroxycholesterol, show a progressive motor neuron degeneration¹².

These observations raise the intriguing possibility that disrupted cholesterol metabolism is closely related to the molecular underpinnings of various neurodegenerative diseases. However, it has yet to be clarified whether cholesterol itself, its metabolites or both have a major role in the maintenance of neuronal function. Moreover, it is also unclear whether augmenting brain cholesterol is capable of protecting debilitated neurons, given the detrimental effects of cholesterol, such as atherosclerosis.

Further basic research is necessary to understand how cholesterol dysregulation impairs neuronal functions and to identify therapies targeting cholesterol-dependent neuron damage. It is particularly important to develop methods to selectively manipulate cholesterol metabolism in the brain and to evaluate the effect and safety of such interventions.