Disruption of chaperone-mediated autophagy by alpha-synuclein causes a buildup of MEF2D, according to Science paper.
A group of researchers say that they have uncovered a pathway that modulates cell loss and survival in Parkinson’s. Working with a mouse model of the disease and cell cultures, they found that an accumulation of alpha-synuclein interferes with cells’ recycling of a protein called MEF2D, leading to cell death.
Parkinson’s is characterized by clumps of aggregated proteins inside cells, which suggests underlying problems in protein recycling and waste disposal. The research team thus wanted to decipher how disrupting the process of recycling kills brain cells.
Some inherited forms of the disease have been linked to mutations in the gene for alpha-synuclein or triplications of the gene, which produce either a toxic form of alpha-synuclein or more alpha-synuclein than normal.
During chaperone-mediated autophagy (CMA), certain selected proteins are funneled into lysosomes. In a neuronal cell line, the investigators found that CMA regulated the activity of MEF2D, a transcription factor needed for proper development and survival of brain cells. MEF2D was continuously shuttled to the cytoplasm where it interacted with the chaperone Hsc70 and was degraded. Inhibition of chaperone-mediated autophagy caused accumulation of inactive MEF2D in the cytoplasm.
The research team also observed that MEF2D levels were increased in the brains of alpha-synuclein transgenic mice and patients with Parkinson’s disease. Investigating further, they found that wild-type alpha-synuclein and a Parkinson’s disease–associated mutant disrupted the MEF2D–Hsc70 binding and led to neuronal death.
Thus, chaperone-mediated autophagy modulates the neuronal survival machinery, and dysregulation of this pathway is associated with Parkinson’s disease.
Following the influence of alpha-synuclein on MEF2D may be a way to connect the various genetic and environmental risk factors for Parkinson’s, even if CMA is not the sole mechanism, says senior author Zixu Mao, Ph.D., associate professor of pharmacology at Emory University School of Medicine. “It may be that various stresses impact MEF2D in different ways,” he says. “We think this work provides an explanation that ties several important observations together.”
Researchers from Johns Hopkins University and the University of Alabama, Birmingham were also involved in this study. Their results are published in the January 2 edition of Science.
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