Isacson study reveals more details on the effects of Huntington's Disease

March 28th, 2005

Ole Isacson

Ole Isacson

Huntington's disease is caused by mutations in a single gene. The mutation leads to an abnormal form of a protein called huntingtin, which accumulates into toxic deposits inside nerve cells. Researchers have focused their efforts on understanding why mutant huntingtin accumulates and how it might damage brain cells.

Ole Isacson, Dr.Med.Sci., director of the Neuroregeneration Laboratory in the Mailman Research Center, has published a paper in the Annals of Neurology postulating an explanation for how the damage occurs. One current theory notes that there is a breakdown in the clearance of abnormal proteins in Huntington's disease. Normally, the ubiquitin-protesome system (UPS) tags defective proteins and disassembles them. In Huntington's disease, however, the UPS does not appear to be fully functional, leaving defective proteins like huntingtin to accumulate. Furthermore, researchers have also found other critical defects in the brain cells of Huntington's patients, including a scarcity of molecules called neurotrophins that nourish brain cells, as well as problems with mitochondrial activity.

Isacson and his colleagues found that the UPS is not working properly in the skin cells of Huntington's disease patients either, yet there is no evidence that this malfunction harms the skin cells. Similarly, the researchers found abnormalities in neurotrophins and mitochondrial operation in many unaffected areas of the brain in Huntington's disease. It thus appears that only a few select groups of cells in the brain fail to adapt to this combination of problems, and the resultant degeneration of these cells leads to Huntington's disease.

An important implication of the study is that the mutant huntingtin protein does not just have one negative effect on brain cells, but several. This may mean that therapeutic strategies will have to take the form of combinations of drugs that address the different processes.

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