Two laboratories at Johns Hopkins Medical Institutions report in today's issue of Science that they have not only discovered the biological flaw behind Huntington's disease but also were able to correct it in cultured cells. The findings could eventually lead to drug treatments for the devastating neurodegenerative condition, characterized by jerky, involuntary movements and progressive dementia. And more broadly, the results may shed light on a class of disorders known as triple-repeat diseases, to which Huntington's belongs.

Scientists discovered the gene responsible for Huntington's diseaseand its defectback in 1993. In affected individuals, this stretch of DNA has extra repeats of three amino acids, namely cytosine, adenine and guanine (CAG). The more CAG repeats a person has, the earlier the onset of the disease. What researchers didn't know was how the gene's product, a protein called huntingtin, killed nerve cells in a brain region known as the corpus striatum, thus creating the symptoms.

Christopher A. Ross and his colleagues suspected that the abnormally shaped huntingtin protein produced by a mutant gene somehow "hijacked" a smaller regulatory protein, CPB. "Without CBP," doctoral student Frederick C. Nucifora, Jr., says, "a pathway crucial for cell survival never gets turned on."

To test the idea, the scientists attached colored fluorescent markers to DNA, huntingtin and CBP inside cells to which they added the mutant Huntington's genes, as well as inside live mice carrying the mutant human gene and postmortem brains from patients. In each case, they were then able to watch abnormal huntigtin keep CBP from doing its job. The top image shows a nerve cell, in which the DNA is blue and the CBP in it is pink; normal huntingtin protein appears green outside the nucleus. In the bottom image, however, the orange clump outside the nucleus is huntingtin bound to CBP.

Taking things a step further, Ross's team next engineered a form of CBP lacking the molecular areas that bind to abnormal huntingtin. When they introduced this bogus CBP and mutant Huntington's genes into cultured cells, the CBP went about its business unhindered. "Instead of degenerating," Ross explains, "cells in these cultures remained healthy. We were able to rescue them completely." The group now plans to test the success of the engineered CBP in a live mouse model.