Brain cell death remains unsolved mystery.

If detectives found several corpses with bullet holes through the heart, they'd be surprised if autopsies showed that the deaths were actually from poisoning.

Similarly, when scientists last year found that people with neurodegenerative disorders such as Huntington's disease have brain cells stuffed with unusual clumps of mutant proteins, many simply assumed that the abnormal buildup inside the cells' nuclei caused the cell death characteristic of the illnesses (SN: 8/16/97, p. 102). That clue may have been misleading: Two studies in the Oct. 2 Cell suggest that the clumping is a largely irrelevant, perhaps even protective, cellular phenomenon.

In the first study, scientists genetically engineered mice to have the mutant gene responsible for spinocerebellar ataxia type 1 (SCA1), one of the diseases in which mutant proteins clump inside cells' nuclei. In some cases, the researchers had modified the gene so that the protein it encodes no longer sticks so readily to other copies of itself. Indeed, the mutant proteins didn't form discernible clumps inside nuclei. Nevertheless, the mice came down with typical symptoms of SCA1.

The proteins must still get into the nucleus to wreak havoc, the investigators found. They disabled the part of the mutant SCA1 gene that encodes the signal for its protein to move into the nucleus. Mice with this altered gene developed no disease symptoms. "If you block the protein from getting into nucleus, you have a cure," says Harry T. Orr of the University of Minnesota in Minneapolis who headed the team that created the mice.

In the second study, Frederic Saudou of Children's Hospital in Boston and his colleagues added the mutant gene responsible for Huntington's disease to rat brain cells grown in the laboratory. The investigators found that the protein encoded by the mutant gene triggers suicide in the same types of brain cells that die in patients with the disease.

Curiously, more cells committed suicide when Saudou added the gene for an enzyme that inhibits the aggregation of the mutant proteins. Saudou's colleague Michael E. Greenberg suggests that the clumps may protect nuclei from toxic effects of the unbound mutant proteins. "The clumps could be an effort to dispose of the protein," he says.

When the team modified the disease gene so that the protein has a signal that prevented it from staying in the nucleus, the brain cells didn't develop aggregates inside their nuclei and didn't die as often.

This cellular study is difficult to relate to the illness, suggests Michael R. Hayden of the University of British Columbia in Vancouver, because the protein encoded by the Huntington's disease gene can also clump inside the cell but outside the nucleus and may damage the brain cell without killing it.

Researchers caution that small protein clumps that went undetected in the experiments could still play a role. "It's a little too early to sort out what the answer is," says Christopher A. Ross of Johns Hopkins Medical Institutions in Baltimore.

"The aggregates clearly are not the whole story," adds Hayden.