Cholesterol and Huntington’s Disease

What is cholesterol and what does it do?^

Cholesterol is a lipid molecule present in all animals. It is largely found in cell membranes, and there is a smaller amount circulating in the blood stream and stored inside cells. Cholesterol has a number of important functions. It is a key structural component of cell membranes, maintaining their fluidity and stability, and enabling important processes such as endocytosis. It is also important for the metabolism of fat-soluble vitamins, the manufacture of bile salts and the synthesis of vitamin D and steroid hormones. The synthesis of vitamins and hormones takes place in endocrine cells, while bile salts are generated in the liver.

Recently a small number of papers have shown that HD patients have altered levels of cholesterol in nerve cells. Since cholesterol plays a key role in the maintenance of healthy neurons, the disruption of normal cholesterol levels in HD patients may be a significant cause of neuron death and dysfunction.

Where does cholesterol come from?^

There are two major ways for our bodies to get cholesterol; it can be synthesized in the body, or obtained from the diet. Normally, our bodies take advantage of both methods of getting cholesterol. On average, a 150 pound person will synthesize about 1 gram of cholesterol per day and intake 200-300 milligrams through their diet.

The highest rate of cholesterol synthesis by the body occurs in the liver, although cholesterol is also made in the intestines, adrenal glands, CNS, and reproductive organs. Other cells can produce cholesterol, but typically in much lower amounts.

Cholesterol is found in all animal foods including meat, poultry, fish, seafood, eggs, and dairy. Cholesterol is not found in plants, so foods like fruits, vegetables, grains, nuts and seeds do not raise cholesterol levels. It is partly because we synthesize so much of our own cholesterol that excess dietary cholesterol is not necessary and can be harmful in a variety of ways.

In this chapter, our goal is to first provide a general review on cholesterol and its activity in the human body, and then look at its relationship to Huntington’s disease.

HDL and LDL^

Most people have heard of a distinction between two types of cholesterol: high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. HDL is commonly referred to as “good” cholesterol, while LDL is called “bad” cholesterol. More precisely, HDL and LDL are not simply different types of cholesterol, but rather alternative groups of lipids and proteins that transport the cholesterol throughout the body in the bloodstream. Molecules such as HDL and LDL are needed to carry cholesterol because it is a hydrophobic molecule and therefore cannot dissolve in blood and travel through the bloodstream on its own.

But if HDL and LDL are just alternative cholesterol carrier molecules, why is one considered good and the other bad? Medical studies have noted that high levels of LDL are associated with an increased risk of cardiovascular disease, whereas high levels of HDL are associated with decreased risk of cardiovascular disease.

How exactly does HDL produce beneficial effects and LDL produce harmful effects? LDL is the major cholesterol carrier in the blood and is responsible for delivering cholesterol to cells in the body. High levels of LDL cholesterol in the blood contribute to the formation of plaque. Plaque is a thick, hard deposit of fat, cholesterol and other substances that clogs arteries and causes atherosclerosis. If arteries become severely clogged with plaque, oxygen-carrying blood may not reach be able circulate around the body- which can lead to heart attack or stroke. Approximately one fourth of blood cholesterol is carried by HDL. HDL is believed to protect against atherosclerosis by carrying cholesterol away from the blood (so it cannot contribute to plaque formation) or even removing excess cholesterol from plaque already built-up in the arteries. HDL usually delivers cholesterol to the liver or endocrine cells, where it will be used in the synthesis of steroids or bile salts, and ultimately removed from the tissue and bloodstream.

Cholesterol as a Risk Factor for Heart Disease^

When our cholesterol levels are tested, they are shown in milligrams per deciliter of blood (mg/dL). The American Heart Association classifies anyone with total cholesterol greater than or equal to 240 mg/dL as belonging to a high risk category. They recommend that those with a total cholesterol level in this high range get a complete fasting lipoprotein profile done. This test measures LDL, HDL, and triglyceride levels. Triglycerides are another contributor to atherosclerosis. The target HDL level is greater than 40 mg/dL, the target triglyceride level is less than 150 mg/dL, and the target total cholesterol level is less than 240 mg/dL.

Cholesterol and Triglyceride Levels (mg/dL)

There are several ways to lower cholesterol levels that are too high. The best methods are usually lifestyle changes. These can include dietary changes such as eliminating foods that are high in saturated fat, trans fat, and cholesterol and increasing the consumption of fruits, vegetables and grains. Exercise is also an important way to reducing the amount of cholesterol in our bodies. By exercising for 20-30 minutes each day we use up greater amounts of fats and other energy molecules that are stored in our bodies. Additionally, there are medications that help lower cholesterol. These medications usually employ one of two general strategies. They either block the synthesis of cholesterol within the bodies’ cells or they prevent cholesterol uptake in the intestine, forcing ingested cholesterol to pass through the body and never be absorbed. The best way to stay healthy is to make sure you have had your cholesterol tested and, if it is too high, to follow your doctor’s instructions for lowering it.

Cholesterol in the CNS^

The CNS contains a large amount of cholesterol, as cholesterol is needed for the growth and maintenance of myelin, as well as neuron and glial cell membranes and for the formation of new connections between cells. However, the CNS is unique in that there is no evidence that it obtains any of its cholesterol from the blood. Instead, cells in the CNS synthesize all of their own cholesterol. In fact, the rate of cholesterol synthesis in the CNS exceeds the need for new cholesterol, so that some cholesterol must move out of the CNS through excretory pathways.

It is not easy for molecules to enter the CNS. Tightly joined endothelial cells found in the capillary network within the brain prevent many molecules from moving from the blood to the CNS. This blood-brain barrier makes it unlikely that cholesterol carried in lipoproteins could reach the CNS unless there were specific transporters in the endothelial cells of the vessel walls. Currently there is no evidence that existing transporters in those endothelial cells actively uptake lipoprotein-transported cholesterol.

Relating cholesterol to Huntington’s disease^

A few studies have recently investigated the role of cholesterol in HD and have suggested that HD may disrupt the normal cholesterol homeostasis in the brain. These research articles propose that the altered huntingtin protein may cause a change in intracellular levels of cholesterol in neurons by disrupting at least two cellular mechanisms: endocytosis and cholesterol biosynthesis. Ultimately, these cellular changes may lead to dysfunction or death of the striatal neurons and reflect another pathway or mechanism by which the mutated huntingtin protein affects the cell and causes neurodegeneration.

Cholesterol Accumulation and Inhibited Endocytosis^

A study by Trushina et al. has reported that the mutant huntingtin protein inhibits a specific type of endocytosis in striatal neurons. These neurons are also shown to have strikingly high intracellular levels of cholesterol.

Mutant huntingtin has been previously shown to interact with clathrin, which is a major protein involved in endocytosis. In this study however, a different protein has been implicated in the disruption of endocytosis in HD. It has been demonstrated that the mutant huntingtin protein interacts with the protein caveolin-1 (cav1), a key molecule in a different endocytotic pathway (called caveolar-related endocytosis). The interaction of mutant huntingtin protein and cav1 inhibits caveolar-related endocytosis and also causes an accumulation of cholesterol within neurons.

Examination of mouse tissue and HD striatal cell cultures revealed the accumulation of intracellular cholesterol. Researchers found that using siRNA to knockdown cav1 translation prevents cholesterol accumulation. For more on siRNA techniques, click here. This occurred only in the continued presence of mutant huntingtin protein, suggesting that it is something specifically about the nature of the interaction between altered huntingtin and cav1 that disrupts normal cholesterol homeostasis, and not simply the lack of cav1 altogether. It was also observed that in all cases clathrin-dependent endocytosis was normal, indicating that the mechanism of cholesterol accumulation was specific to the disruption of the caveolar-related pathway.

How is cholesterol biosynthesis affected?^

In another recent paper, by Valenza et al., Huntington’s disease has been shown to decrease cholesterol biosynthesis in nerve cells. The presence of altered huntingtin in these cells is correlated with significantly lower total cholesterol mass. This was observed in mouse tissue and in cultured striatal neurons expressing a fragment of the mutant huntingtin protein.

Mutant huntingtin affects the transcription of genes crucial to cholesterol synthesis. The altered huntingtin protein interacts with binding proteins called sterol regulatory element -binding proteins (SREBPs) and prevents these proteins from entering the nucleus. These proteins usually bind to DNA and promote transcription of many different genes important for synthesizing cholesterol. Mutant huntingtin has a strong effect on SREBPs; the proteins are reduced by 50% in the nucleus of HD cells. Reduction of the SREBPs results in significantly less transcription of the genes involved in cholesterol biosynthesis, which ultimately reduces total cholesterol.

Large changes in the levels of intracellular cholesterol will eventually lead to disruption of cellular homeostasis. Research with HD cell line models has shown that the addition of exogenous cholesterol to cultured striatal neurons expressing mutant huntingtin joined to a green fluorescent protein will prevent these neurons from dying.

Implications^

Cholesterol is essential for promoting synapse formation and maintaining membrane integrity in CNS neurons. It is also a major component of myelin and important for optimal neurotransmitter release. Because cholesterol plays such a major role in CNS growth, development, and maintenance, disruptions of cholesterol homeostasis can have negative consequences. Accumulation and depletion of intracellular cholesterol in neurons are both possible mechanisms contributing to neuron dysfunction in these HD models. However, the findings are limited to HD cell models and postmortem HD tissue. This work now needs to be followed up by investigating these changes in HD patients to see whether similar dysfunction occurs.

If studies in human subjects found a similar dysfunction in cholesterol homeostasis, it might suggest that adjusting the cholesterol levels in neuronal cells could be investigated as a potential treatment for HD. Future research may aim to discover how to transport cholesterol across the blood-brain barrier and whether cholesterol therapy could be one way of slowing or halting neuronal cell death in HD.

It is interesting to note that similar defects in caveolar-related endocytotic pathways and perturbations of cholesterol homeostasis have been implicated in other neurodegenerative diseases related to HD like Alzheimer’s disease and Parkinson’s disease.

Summary^

Recent research has suggested that disruptions in cholesterol homeostasis could be important in explaining how the HD mutation causes neurodegeneration. However, cholesterol’s role in the disease is still not fully understood. It might seem strange that HD has been linked to both intracellular cholesterol accumulation and depletion. One current hypothesis is that different stages of the disease are characterized by different disruptions to cholesterol homeostasis. Future research should shed light on the connections between these different disruptions and normal cholesterol activity.

For Further Reading^

• American Heart Association website at http://www.heart.org/HEARTORG/.A very user-friendly site with basic information about cholesterol and recommendations for a healthy lifestyle.
• Dietschy and Turley. “Cholesterol metabolism in the central nervous system during early development and in the mature animal.” Journal of Lipid Research 2004. 45: 1375-1397.A review of cholesterol metabolism in the CNS.
• Trushina et al. “Altered huntingtin inhibits clathrin-independent endocytosis and causes accumulation of cholesterol in vitro and in vivo.” Human Molecular Genetics 2006. 15: 3578-3591.A fairly technical article describing the research identifying HD’s affect on endocytosis.
• Valenza et al. “Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease.” The Journal of Neuroscience 2005. 25:9932-9939.Another fairly technical article describing the research behind discoveries relating to cholesterol biosynthesis disruption.
• Valenza and Cattaneo. “Cholesterol dysfunction in neurodegenerative diseases: Is Huntington’s disease in the list?” Progress in Neurobiology 2006. 80: 165-176.A scientific article providing a good overview of how cholesterol is tremendously important for CNS functioning and attempting to analyze the role cholesterol might play in HD.