Cholesterol Transport Dysfunction Implicated in Huntington Disease

OBSERVATION THAT AN EXCESS OF CHOLESTEROL-mediated by interaction between the mutant huntingtinprotein (mHtt) and a protein associated withcholesterol transport-that accumulates in the brainmay eventually guide researchers in how to intervenein Huntington disease (HD) pathology. A team fromthe Mayo Clinic, led by Cynthia McMurray, PhD, amolecular biologist in the Department of Pharmacology,found excessive amounts of cholesterol in striatalneurons in both cell cultures and in specimens takenfrom animal models of HD. That is, the researchersstate in their paper published in the December issueof Human Molecular Genetics, that mHtt inhibits endocytosisin primary striatal neurons.

The research team showed that mHtt interactswith caveolin-1, the principal structural protein ofcaveolae, the small vesicles that transport cholesterolthrough neuronal membranes. When the investigatorssuppressed expression of caveolin-1, accumulationof cholesterol in neurons expressingmHtt was inhibited.

The researchers believe that their findings arehighly relevant to understanding the neurotoxic effectsof HD. "Fully understanding the mechanismof toxicity is the key to developing treatments," saidMcMurray.

For more information, see: Trushina E, Singh RD,Dyer RB, et al. Mutant huntingtin inhibits clathrinindependentendocytosis and causes accumulationof cholesterol in vitro and in vivo. Hum Mol Genet.2006;15:3578-3591.
-Dee Rapposelli