Scientists at Emory University School of Medicine have announced the identification of a mechanism behind the development of clumps of aggregated proteins inside cells, a hallmark of Parkinson's and other neurodegenerative diseases.
The researchers say that the build up of these clumps, also known as Lewy bodies, may be prevented by targeting a survival circuit called MEF2D, which is sensitive to the main component of Lewy bodies, a protein called alpha-synuclein.
Writing about their study in the journal Science, they have revealed that in cell cultures and animal models of Parkinson's, an accumulation of alpha-synuclein interferes with the cell's recycling of MEF2D, leading to cell death.
The team have found that MEF2D is especially abundant in the brains of people with Parkinson's.
"We've identified what could be an important pathway for controlling cell loss and survival in Parkinson's disease," says senior author Dr. Zixu Mao, associate professor of pharmacology at Emory University School of Medicine.
He says that future studies may lead to the identification of effective drugs to regulate MEF2D, allowing brain cells to survive toxic stresses that impair protein recycling.
While most Parkinson's cases do not have any obvious genetic cause, some inherited forms of the disease may be linked to mutations in the gene for alpha-synuclein or triplications of the gene, which cause the brain to produce either a toxic form of alpha-synuclein or more alpha-synuclein than normal.
"Somehow it's toxic, but alpha-synuclein isn't part of the cell's machinery of death and survival," Mao says.
During their study, Mao and his colleagues found that mice that artificially overproduce alpha-synuclein had elevated levels of apparently inactive MEF2D in their brains.
The researchers also observed that MEF2D protein levels were higher in the brains of Parkinson's patients than in controls.
Based on their observations, they came to the conclusion that following the influence of alpha-synuclein on MEF2D may be a way to connect the various genetic and environmental risk factors for Parkinson's.
"It may be that various stresses impact MEF2D in different ways. We think this work provides an explanation that ties several important observations together," he says.