Proceedings of the National Academy of Sciences, July 29, 2009

It has long been known that "Lewy bodies", one of the hallmarks of Parkinson's disease and related types of neurodegenerative conditions, are formed from the aggregate accumulation of the synaptic protein alpha-synuclein. It has also been understood that the progression of such diseases is associated with the spreading of the Lewy bodies, which continue to infiltrate more and more regions of the brain. It has not previously been understood, however, exactly how the Lewy bodies are able to spread. Now, researchers are one step closer to a full elucidation of the underlying cellular and molecular mechanisms by which Lewy bodies ultimately invade the entire brain.

At the crux of the phenomenon is the neuron-to-neuron transmission of the alpha-synuclein itself - a new discovery made by collaborating scientists at the UC-San Diego School of Medicine and Konkuk University in Seoul, South Korea. According to Dr. Paula Desplats, lead author of the study and project scientist in the UC-San Diego Department of Neurosciences, "This 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."

The discovery is believed to have important implications for the use of stem cell therapies in the treatment of Parkinson's disease and other "proteinopathies", since stem cells that are transplanted into the brains of patients are also vulnerable to eventual degeneration if a number of conditions are not suitable. As Dr. Eliezer Masliah, professor of neurosciences and pathology at the UC-San Diego School of Medicine, explains, "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 alpha-synuclein or by making them more efficient in clearing the accumulated alpha-synuclein."

In most though not all Parkinson's patients, the progression of alpha-synuclein is observable in a predictable pattern which begins in the lower brainstem and spreads first to the limbic system before ultimately attacking higher level cognitive functions in the neocortex. Prior to this study, previous findings had indicated that alpha-synuclein also spreads to transplanted neurons in Parkinson's patients, an observation which led to a hypothesis of disease progression via neuron-to-neuron transmission. In the current study, which was specifically designed to test that hypothesis, the scientists discovered that the alpha-synuclein is transmitted between neurons via a process known as endocytosis, in which cells are able to absorb proteins from the extracellular media through their cell membranes. In addition to demonstrating that the accumulation of alpha-synuclein can be diminished by blocking the endocytic pathway, the scientists also found that inhibited lysosomal activity accelerates the accumulation of alpha-synuclein, since normal lysosomes would ordinarily help remove the accumulated aggregates. The scientists then demonstrated in a transgenic animal model how the alpha-synuclein is transmitted directly from host to grafted cells. Despite the fact that the laboratory animals had received fresh, healthy stem cells, within four weeks of the transplantation their brains had been overrun with Lewy bodies. Such findings would explain why human Parkinson's patients who had received neuronal transplants usually succumb to the disease anyway, since the Lewy bodies that characterize Parkinson's are still able to ravage the newly transplanted neurons.
As a result of these findings, researchers are now turning their attention to the strategic development of mechanisms by which stem cell therapy may be administered to Parkinson's patients in conjunction with the blocking of endocytic pathways, and also in conjunction with the enhancement of normal lysosomal activity.