Researchers have gained fresh insights into how a mechanism whereby the formation of aggregates called Lewy bodies, a hallmark of Parkinson's, spreads in the brain as the disease progresses.
Writing about their work in the Proceedings of the National Academy of Sciences (PNAS), the researchers at the University of California, San Diego School of Medicine and Konkuk University in Seoul, South Korea, claim that theirs is the first study to show neuron-to-neuron transmission of alpha-synuclein, the synaptic protein the accumulation of which results in the formation of Lewy bodies in the brain.
"The discovery of cell-to-cell transmission of this protein may explain how alpha-synuclein aggregates can pass to new, healthy cells. We demonstrated how alpha-synuclein is taken up by neighboring cells, including grafted neuronal precursor cells, a mechanism that may cause Lewy bodies to spread to different brain structures," said first author Paula Desplats, project scientist in UC San Diego's Department of Neurosciences.
"Our findings indicate that the stem cells used to replace lost or damaged cells in the brains of Parkinson's disease patients are also susceptible to degeneration. Knowledge of the molecular basis of the intercellular transmission of alpha-synuclein may result in improved stem-cell based therapies with long-lasting benefits, by preventing the grafted cells to uptake a-synuclein or by making them more efficient in clearing the accumulated alpha-synuclein ," said Dr. Eliezer Masliah, professor of neurosciences and pathology at UC San Diego School of Medicine.
Working in collaboration with South Korean expert Seung-Jae Lee, the researchers first looked at neural precursor cells in culture, co-culturing them with neuronal cells expressing alpha-synuclein.
After 24 to 48 hours, the aggregated alpha-synuclein was evident in the precursor cells, results suggesting cell-to-cell transmission.
The research team used specific inhibitors, and discovered that alpha-synuclein is transmitted via endocytosis, the normal process by which cells absorb proteins from the extracellular media by engulfing them within their cell membrane. Blockage of the endocytic pathway resulted in lesser accumulation of alpha-synuclein.
The researchers also found that failure of the quality-control systems of the cell contributes to the observed accumulation of alpha-synuclein in recipient cells.
This, according to them, is due to inhibited activity of cell particles called lysosomes, which would usually degrade and remove aggregates, resulting in their increased formation.
The researchers then studied whether alpha-synuclein could be transmitted directly from host to grafted cells in a mouse model of Parkinson's disease. They grafted the brains of the mouse model with fresh, healthy stem cells. Within four weeks, cells containing Lewy body-like masses were quite common, supporting the cell-to cell transmission mechanism.