Cholesterol and HD

An investigation into how HD affects cholesterol homeostasis

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.

Last Modified: 07/07/2007

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