Brandeis scientists have made groundbreaking advances in understanding how the regulations of a novel gene during the cell cycle can lead to a rare familial case of the early onset of Parkinson's disease. Parkinson's is the most common neurodegenerative disease after Alzheimer's, affecting about 1 million Americans. Most of those affected develop the disease sporadically, after age 60, but a small percentage get the disease much earlier, from inherited mutations in one of several genes.
Post doctoral fellow Mark Wilson and Jennifer Collins, Ph.D. '04, together with Courtney St. Amour '03, discovered how DJ-1, a recently discovered Parkinson's gene, may be involved in protecting some cells from stress and defects in the cell's cycle, leading to the disease's progression. The new Brandeis research is under the leadership of Gregory A. Petsko, the Gyula and Katica Tauber Professor of Biochemistry and Molecular Pharmacodynamics and Director Rosenstiel Basic Medical Sciences Research Center, and Dagmar Ringe, Lucille P. Markey Professor of Biochemistry and Chemistry.
"DJ-1 is a protein expressed in every cell, "said Petsko. "Yet the only cells affected by mutations that lead to a loss of function of DJ-1 are found in a certain sub-set of neurons in the middle of the brain."
Although the protein DJ-1 is highly abundant in all cells, its biological functions, mechanisms of action, and its implication in Parkinson's disease are not well understood. By tracking its role in the cell cycle and any associated defects in cellular behavior caused by the loss of its function, the researchers hope to provide insights into the common pathway that causes disease progression.
Using a simple, one celled organism - Saccharomyces cerevisiae, or bakers yeast the team has created a model system that allows them to study the function of some of the corresponding genes in the human genome. This system led them to investigate a yeast gene that turned out to be similar to human DJ-1.
"Mammalian cells aren't so easy to work with - you can easily work with yeast cells and they have many of the same properties as human cells," said Petsko. "It's easier to do biochemistry on yeast cells and they can help identify human genes that share the same function."
Applying this system, the scientists have been investigating the hypothesis that the quiescent or resting state of the cell makes it more vulnerable to the loss of proteins like DJ-1.
"There is something about the quiescent state of the cell, we think, that makes it more vulnerable to the loss of DJ-1. Neurons are quiescent cells. And in collaborative work with Mark Cookson at the NIH, we've shown that loss of this protein in mammalian cells makes the cells much more sensitive to certain types of stress, stress that occurs more frequently in quiescent cells like neurons. The discovery may be a link to uncovering how mutations leading to the loss of function of this protein cause increased cellular oxidative stress and ultimately leads to the development of the disease."
The researchers hope to discover the intricate mechanisms that link the loss of function of the mutated DJ-1 protein with neurodegeneration at the cellular level. This may also provide insights to common pathways of other diseases such as Alzheimer's, Lou Gehrig's and many other neurodegenerative diseases.
"Ultimately our research may help lead to medicine that people can take as they age that will either slow down or prevent the disease," said Petsko.