Major Clue Links Seven Deadly Syndromes

Researchers have discovered a landmark clue to what causes the nerve cell loss in a group of seven deadly neurological conditions, the most common of which are Huntington's disease and Machado-Joseph disease (MJD). The work, to appear in the August issue of Neuron and tomorrow's issue of Cell, could lead to new treatments and perhaps cures, for these ailments, which are characterized by wild, uncoordinated movements.

All of the diseases, which cause the death of brain cells involved in controlling body movements, have recently been traced to specific genes. These genes share a striking feature: a large increase in the length of stretch of DNA in which the genetic code word (CAG) for the amino acid glutamine is repeated numerous times. Since the most severely affected patients have the longest repeats, researchers assumed that these extra glutamines, which end up in the genes' protein products, somehow led to the death of nerve cells, but nobody knew how.

Searching for an answer, neuroscientists Henry Paulson, Randall Pittman, and their Pennsylvania colleagues set out 2 years ago to look at the distribution of the MJD gene's protein product in normal brains and those of MJD patients. Examining post-mortem tissue, the researchers discovered that the protein is normally scattered through the cytoplasm of brain cells. But in MJD patients, it collects in large clumps, clogging cell nuclei in the affected brain areas. Then, to test the notion that a CAG repeat could cause this nuclear clumping, the team inserted a shortened MJD gene containing a long CAG repeat (78 CAGs) into cultured cells and watched the protein product migrate into the nucleus, aggregate there, and recruit the normal MJD protein into a tangle. That did not happen with the normal MJD gene, with just 28 CAG repeats.

Evidence that the protein aggregation in the nucleus can indeed cause the neurodegeneration seen in these triplet repeat diseases comes from work appearing in the tomorrow's Cell. When Gillian Bates at Guy's Hospital, London and Stephen Davies at University College in London and their colleagues examined the brains of transgenic mice endowed with a DNA encoding 150 of these glutamine repeats, they found that the protein started out, at birth, in the cytoplasm of the animals' brain cells and then gradually migrated to cell nuclei and clumped there. What's more, by 2 months of age, when the nuclei became sufficiently clogged, the mice began shuddering, shaking, and showing other symptoms reminiscent of humans with Huntington's disease. In a second Cell paper, another research team showed, in cell culture, that protein fragments with the long glutamine repeat will clump together in masses.

The suite of new findings provides a critical window on the mechanism for CJD and similar triplet repeat diseases like Huntington's. "There was a huge chasm in knowledge between the expression of the CAG repeat and cell death," says Pittman. "Now we know that these proteins aggregate and that they do so in the nucleus." Indeed, the glutamine repeats themselves are the likely glue.

"It's a radically exciting finding, the best thing that's happened in any of these diseases in a long time," says Nancy Wexler, president of the Hereditary Disease Foundation in Santa Monica, California, and a neuropsychologist at Columbia College of Physicians and Surgeons in New York City. She adds that the work lays bare "a wonderful target of attack, because disaggregating the [protein bundles] could cure the disease." Whether that is possible remains to be seen. But the new findings have narrowed the scope for the search for answers to Huntington's and the other diseases. "There used to be 100 possibilities; now there are just a few," Pittman says.