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Yeast Point to Multiple Mutations in Neurodegenerative Disease
  
By Nancy Touchette

Common baker's yeast, Saccharomyces cerevisiae.

The causes of most human diseases have been difficult to pinpoint because they are likely to involve defects in multiple genes. Now researchers are turning to a new technique to find gene mutations that by themselves are harmless, but in combination with other mutations can impair the cell and cause disease.

Two groups of researchers have collaborated to identify gene combinations that may play a role in two devastating neurological disorders—Huntington’s disease and Parkinson’s disease. They speculated that the diseases might share some common pathways and common gene mutations because they both involve the formation of protein deposits in the brain.

Their results show that the processes that lead to protein deposits are probably different for the two diseases. “There is no common pathway,” says researcher Paul Muchowski of the University of Washington in Seattle.

Muchowski has used yeast to study genes that may contribute to Huntington’s disease in humans. Huntington’s disease is caused by mutations in the huntingtin gene, but other gene mutations may affect the age of onset and severity of disease.

The collaboration also demonstrates how a collection of nearly 5,000 yeast strains, each of which has one gene deleted, may be used to identify possible new target genes that may combine to cause disease in humans. Yeast are valuable tools for understanding human cells, because many of the genes important in yeast cell function have similar versions in human cells.

“This is a quick, cheap way to test the functions of genes that might be involved in human disease,” says Tiago Fleming Outeiro, one of the Parkinson’s researchers.

Each mutant strain can grow perfectly well by itself. But if a mutated form of a second gene is added to the cell, some of the yeast strains die. While a single mutation may have no effect in yeast, a double mutation may be lethal. But which genes, in combination, cause disease in humans?

Muchowski’s work on Huntington’s disease caught the attention of Susan Lindquist and Outeiro, both of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, who were studying the role of the α-synuclein gene in Parkinson’s disease.

Together, the researchers added mutant forms of either huntingtin or α-synuclein to each of the 5,000 yeast strains and looked for cells that died. Knowing which gene was missing in the strain allowed them to identify possible genes that, when mutated, could contribute to disease when either huntingtin or α-synuclein is also mutated.

The researchers found 52 genes that collaborate with the huntingtin gene to kill yeast cells and 86 genes that collaborate with α-synuclein, they reported in Science. The huntingtin-associated genes included those that degrade proteins and respond to stress. Those associated with α-synuclein are involved in trafficking vesicles and metabolizing lipids. The differences imply that different processes lead to the protein deposits involved in the two diseases.

Whether any of the newly identified genes plays a role in human disease remains to be seen. But now it is possible to zero in on promising genes in humans that are similar to those found in yeast.

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Researchers typically hunt for genes that play a role in human disease by comparing the DNA of healthy and affected individuals among families affected by disease. By following the pattern of inheritance of certain DNA “markers” in affected individuals, the location of a particular disease-causing gene on a chromosome can be narrowed down. But this approach often takes years of research.

“Now we can go back and see if any of the genes on our list are mutated in families with a history of disease,” says Muchowski. “It gives us a place to look.”

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Willingham, S. et al. Yeast genes that enhance the toxicity of a mutant huntingtin fragment or α-synuclein. Science 302, 1769-1772 (December 5, 2003).

 

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