New Research in Huntington's Disease

Although other researchers have shown that various intrabodies can protect cells from mutant huntingtin, the Emory team was the first to examine the effects of an intrabody in living mice, says senior author Xiao-Jiang Li, PhD, professor of human genetics at Emory University School of Medicine. Delivering the intrabody to brain tissues in people would be a formidable challenge, because it would require some form of gene therapy. However, it may be possible to use information about the intrabody's structure to find drugs that mimic its effects, Li says.

Disease-causing mutations involve a lengthening of part of the gene for huntingtin, so that it repeats three letters (CAG) of the genetic code dozens of times. Mutant proteins have a region consisting of the same amino acid (glutamine) many times, called poly-glutamine, which makes the proteins clump together inside brain cells. Li says scientists who work on Huntington's have been studying where inside the cell the clumps have their toxic effect: brain cells' nuclei or in their axons and dendrites.

"Our goal here was to create a tool that could distinguish between the accumulation of mutant proteins in the nucleus and the cytoplasm," he says. "The intrabody binds huntingtin proteins with expanded poly-glutamine regions and it only works in the cytoplasm, not the nucleus." The researchers showed that cultured cells that make both the intrabody and mutant huntingtin are able to get rid of the mutant protein faster and have fewer clumps of huntingtin. Even though the intrabody only travels within the cytoplasm, it still alleviated the motor problems of mice that make mutant huntingtin when injected into the striatum, the scientists found.

The striatum is the part of the brain most affected by Huntington's disease. Li says finding an antibody that prefers to bind mutant, aggregated protein could also prove useful in the study of other neurodegenerative disorders, such as Alzheimer's disease or Creutzfeldt-Jakob disease.; Source: Emory University