Emory Report
January 20, 2009
Volume 61, Number 16



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January 20
, 2009
Toxicity mechanism identified for Parkinson’s disease research

By Quinn Eastman

Emory scientists have identified how a disruption of protein recycling can cripple brain cells in Parkinson’s disease.

The results were published in the Jan. 2, 2009 issue of Science.

Neurologists have observed for decades that Lewy bodies, clumps of aggregated proteins inside cells, appear in the brains of patients with Parkinson’s and other neurodegenerative diseases.

The presence of Lewy bodies suggests underlying problems in protein recycling and waste disposal, leading to the puzzle: how does disrupting those processes injure the brain?

One possible answer: by breaking a survival circuit called MEF2D. Researchers led by pharmacologist Zixu Mao have discovered that MEF2D is sensitive to the main component of Lewy bodies, a protein called alpha-synuclein.

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. MEF2D is especially abundant in the brains of people with Parkinson’s, the researchers found.

Most cases of Parkison’s disease are termed sporadic, meaning that there is no obvious genetic cause. But some rare inherited forms of Parkinson’s can be linked to mutations in the gene for alpha-synuclein or triplications of the gene. The mutations and triplications 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.
He and his colleagues studied a process called chaperone-mediated autophagy (CMA), a disposal mechanism for alpha-synuclein.

In CMA, proteins are funneled into lysosomes, compartments of the cell devoted to chewing up discarded proteins. Mao’s team found that over-abundant alpha-synuclein interferes with CMA, causing MEF2D protein levels to rise. When CMA is disrupted, most of the accumulated MEF2D can’t bind DNA. This may indicate that the protein is improperly folded or otherwise modified.

“Even though there’s a lot of it, something is making the MEF2D protein inactive,” Mao says.
Further research could identify drugs that regulate MEF2D, allowing brain cells to survive stresses that impair protein recycling, he suggested.