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Jul 28, 2009

Key to Parkinson’s Pathology May Lie in Cell-to-Cell Transmission of Alpha-Synuclein

  • Neuron-to-neuron transmission of alpha-synuclein could be central to the spread of the Parkinson’s pathology, according to Researchers at the University of California, San Diego School of Medicine and Konkuk University in Seoul, South Korea.

    The group explains how this synaptic protein, which forms aggregates called Lewy bodies in patients’ brains, is taken up by neighboring cells. They believe that this mechanism may cause Lewy bodies to spread to different brain structures.

    The findings will appear in the Proceedings of the National Academy of Sciences on July 29. They may impact research into stem-cell therapy for Parkinson's disease, the scientists point out. “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,” says Eliezer Masliah, M.D., professor of neurosciences and pathology at UC San Diego School of Medicine. 

    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, suggesting cell-to-cell transmission. Using specific inhibitors, the research team also 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. 

    Next, the team tried to determine if alpha-synuclein could be transmitted directly from host to grafted cells in a mouse model of Parkinson's disease. The brains of these mice were grafted with fresh, healthy stem cells. Within four weeks, cells containing Lewy body-like masses were quite common, according to the investigators.

    The hypothesis of disease progression by neuron-to-neuron transmission of alpha-synuclein that prompted this study was supported by findings of two separate reports in 2008. In these studies, autopsies of deceased Parkinson's patients who received implants of therapeutic fetal neurons 11 to 16 years prior revealed that alpha-synuclein propagated to the transplanted neurons.

    In cell culture, 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 is due to inhibited activity of cell particles called lysosomes, which usually degrade and remove aggregates resulting in their increased formation.

     



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