"Good Guy" Proteins Ride in to Save Cells
New research on how the body fights diseases like Huntington's, Parkinson's and Alzheimers could lead to significant advances on treating and perhaps reversing neurodegenerative illness.
Scientists have believed for sometime that certain "good guy" proteins work to rescue healthy proteins from damage by forces that cause cell death. But they've never understood how the good guys, called molecular chaperones do their work.
A research team led by Richard Morimoto, a Northwestern University biologist, devised a tactic to observe the chaperons trying to save healthy proteins in a living cell where several components were affected with Huntington's disease.
"We've made movies now of this process in action", Morimoto said. "It's exciting because it will suggest new ways to help this natural process regain its equilibrium to keep the disease from progressing or, maybe, reversing it".
The work, published in Nature Cell Biology, asked the questions of whether the chaperons help individual proteins in a dying cell and whether that help makes the cell feel better, said Marcy E. MacDonald, an associate professor of neurology at the Harvard Medical School.
"The clear answers from the experiments are 'yes' and 'yes," she said. In Huntington's - and a host of other ailments, including mad cow disease, cystic fibrosis and Creutzfeldt-Jakob disease - trouble starts when proteins get bent the wrong way.
Proteins are adept at bending and unbending, but when bent the wrong way, they stop functioning and, worse, form a clump that attracts healthy proteins that in turn bend and stop working. As the process continues, the cell eventually shuts down and dies. Cell death due to bent proteins is the core cause of most of the neurodegenerative disease, many scientists believe.
"Cells are essentially just bags of proteins, so if the proteins get in trouble, the whole cell gets in trouble," said Morimoto.
Researchers have long been intrigued that chaperones seem to help slow the protein decline, and Morimoto's team set out to study the phenomenon by labeling protein with fluorescent materials to make them give off light.
That enables the scientists to view, using a high-powered microscope, the interactions of proteins in a living cell afflicted with a clump of bent proteins. They noted when ordinary proteins get stuck in a clump, they couldn't get out. But unlike ordinary proteins, the chaperons have the ability to go into and out of the clump without getting stuck.
Furthermore, the chaperons were able to go in and usher out a healthy protein that had become stuck, said Morimoto.
"The word chaperon comes from the French, meaning to prevent inappropriate behavior," Morimoto said. "That usually refers to behavior between boys and girls, but in this case it refers to inappropriate bending behavior by proteins. These chaperones slow down the process whereby proteins lose their ability to function. It is a normal part of how cells maintain their function. In cases where there is diseases, somehow this process has gone awry".
"Morimoto's work was done with worm cells, but it is very significant and points toward further work to be done in human cells," said Harvard's MacDonald. "By establishing that at least one kind of chaperone works to save proteins at risk in cells afflicted with Huntington's disease, the study suggests a broader effect by many chaperones in many diseases," she said.
"The work sets the stage for genetic and biochemical studies in patient samples," MacDonald said.
