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Parkinsonís Clues from Ordinary Bakerís Yeast
  
By Nancy Touchette

Researchers studying Parkinson’s disease have turned to an unlikely tool to understand the disease: common baker’s yeast. The same microbe that causes bread to rise is helping researchers figure out how a normal brain protein turns bad and contributes to disease.

A new study indicates that yeast cells are exquisitely sensitive to levels of a protein involved in Parkinson’s disease, called α-synuclein. Even a modest excess of the protein may clump up and interfere with several cell functions, eventually triggering cell death, and scientists think the same problem may occur in people.

Yeast cells are sensitive to α-synuclein protein (green), which plays a role in Parkinsonís disease. Cells with one copy of the gene (left) are healthy, but two gene copies cause the protein to clump and kill the cells (right).

One of the hallmarks of Parkinson’s disease is the accumulation of protein deposits within the brain. The aggregates, called Lewy bodies, contain large amounts of α-synuclein, a normal cell protein.

Some patients with Parkinson’s disease have mutations in the α-synuclein gene and some patients have extra copies of the normal gene. But most patients have no obvious α-synuclein abnormalities.

Recently, researchers from the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, produced a fluorescent version of α-synuclein in yeast and then watched where the protein travels in the cell. Yeasts carry out many of the basic functions of cells from higher organisms, such as humans, but are easier to work with and provide almost instant results.

The researchers found that when one copy of the human α-synuclein gene is added to yeast cells, the protein attaches to the plasma membrane that surrounds the cell. But when two copies of the gene are added, the protein detaches from the membrane and forms clumps similar to those found in Parkinson’s disease.

ďDoubling the amount of protein in the cell has a very dramatic effect,Ē says Tiago Fleming Outeiro, a graduate student with Susan Lindquist, who led the research. ďThis somehow tips the balance so the protein can’t fold properly and forms aggregates.Ē

The researchers also found that the protein clumps disrupt some of the normal cell functions, including metabolizing lipids and trafficking, or moving vesicles in and out of the cells. Neurons communicate with each other by transporting chemicals packaged in vesicles.

ďOne can imagine that having these clumps of proteins in cells disrupts the normal trafficking that occurs in neurons,Ē says Outeiro. ďAs a result the cell can’t function properly and pathways may be activated that eventually kill the cell. This may be what’s happening in Parkinson’s.Ē

Researchers still don’t know what triggers the α-synuclein excess. However, the results are consistent with studies by Andrew Singleton of the National Institutes of Health in Bethesda, Maryland, who recently found that some patients with a severe form of Parkinson’s carry three copies of the normal form of α-synuclein on one of their chromosomes.

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Fleming, T.F. and Lindquist, S. Yeast cells provide insight into α-synuclein biology and pathobiology. Science 302, 1772-1775 (December 5, 2003).

 

Singleton, A.B. et al. α-synuclein locus triplication causes Parkinson’s disease. Science 302, 841 (October 2003).

 

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