Cholesterol and HD

An investigation into how HD affects cholesterol homeostasis

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.

Last Modified: 02/09/2008

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