Effects of Huntington’s Disease Mutation More Complex than Supposed

Competing theories about why brain cells die in Huntington’s disease may not be competitors after all, according to a report published July 23, 2004, in the early online edition of the Annals of Neurology.

Researchers report finding minor molecular abnormalities of the sort proposed by these different theories in cells throughout the brain and even in the skin. Yet only select groups of cells in a few movement centers of the brain are so vulnerable to these disruptions that they degenerate and die.

The results suggest that therapeutic strategies for Huntington’s–as well as other neurodegenerative diseases such as Alzheimer’s and Parkinson’s–may have to be more complex than previously supposed.

Huntington’s is an inherited, degenerative brain disease marked by movement abnormalities–involuntary, dance-like movements called “chorea” early in the illness and later a gradual loss of the ability to move muscles voluntarily–as well as psychiatric symptoms such as depression and mood swings.

Huntington’s disease is caused by mutations in a single gene. The mutation leads to an abnormal form of the 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.

One prominent theory notes that there is a breakdown in the clearance of abnormal proteins in Huntington’s disease. Normally, a cellular ’garbage’ service called the ubiquitin-protesome system (UPS) tags defective proteins and disassembles them. In Huntington’s disease, the UPS does not appear to be fully functional, leaving defective proteins like huntingtin to accumulate.

However, 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, and problems with mitochondria, the “power plants” that produce energy for cells.

In their study, Ole Isacson, MD, and his colleagues at Harvard University and McLean Hospital explored the relationships between these different cellular processes in different cells inside and outside the brain.

Surprisingly, first author Hyemyung Seo, PhD, and colleagues found that the UPS is not working properly in the skin cells of Huntington’s disease either, yet there is no evidence that this harms the cells. Similarly, the researchers found abnormalities in neurotrophins and mitochondrial operation in many unaffected areas of the brain in Huntington’s disease.

“It appears that only a few select groups of cells in the brain fail to adapt to this combination of problems. The degeneration of these cells leads to Huntington’s disease,” said Isacson.

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.

Mark Cookson, Ph.D, an expert on neurodegenerative disease at the National Institute on Aging in Bethesda, Maryland, believes this study will be of great interest to scientists who study diseases like Alzheimer’s and Parkinson’s, which also feature accumulations of abnormal proteins, problems in UPS ’garbage collection,’ and the death of only certain vulnerable subgroups of cells.

“An obvious follow-up is to look at other neurodegenerative diseases. Presumably, there would be a pattern of cellular deficits parallel to, but distinct from those of Huntington’s disease,” said Cookson.