News ArchivesRead News
How the pathology of Parkinson's disease spreads
Thursday July 30, 2009
Neuron-to-neuron transmission of a-synuclein may cause alpha-synuclein aggregates to propagate
EurekAlert - Accumulation of the synaptic protein alpha-synuclein, resulting in the formation of aggregates called Lewy bodies in the brain, is a hallmark of Parkinson's and other related neurodegenerative diseases.
This pathology appears to spread throughout the brain as the disease progresses. Now, researchers at the University of California, San Diego School of Medicine and Konkuk University in Seoul, South Korea, have described how this mechanism works. Their findings – the first to show neuron-to-neuron transmission of alpha-synuclein – will appear in the Proceedings of the National Academy of Sciences (PNAS) on July 29.
"The discovery of cell-to-cell transmission of this protein may explain how alpha-synuclein aggregates can pass to new, healthy cells," said first author Paula Desplats, project scientist in UC San Diego's Department of Neurosciences. "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."
This insight will impact research into stem cell therapy for Parkinson's disease. "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," said Eliezer Masliah, MD, professor of neurosciences and pathology at UC San Diego School of Medicine. "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 α-synuclein or by making them more efficient in clearing the accumulated alpha-synuclein ."
In a large proportion of Parkinson's disease cases, the aggregation of alpha-synuclein progresses in a predictable pattern – from the lower brainstem, into the limbic system and eventually to the neocortex, the part of the brain responsible for higher level cognitive functions. The hypothesis of disease progression by neuron-to-neuron transmission of alpha-synuclein that encouraged this study was supported by findings of two separate reports in 2008. In these studies, autopsies of deceased Parkinson's patients who had received implants of therapeutic fetal neurons 11 to 16 years prior revealed that alpha-synuclein had propagated to the transplanted neurons.
Collaborating with South Korean researcher Seung-Jae Lee, the UC San Diego 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. 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
Additionally, the researchers 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 would usually degrade and remove aggregates – resulting in their increased formation.
Next, the team tested to determine if alpha-synuclein could be transmitted directly from host to grafted cells in a mouse model of Parkinson's disease. Brains of the mouse model were grafted with fresh, healthy stem cells. Within four weeks, cells containing Lewy body-like masses were quite common, supporting the cell-to cell transmission mechanism.
Recent NewsJul 20 - Parkinson’s DREAM Challenge Uses Mobile Sensor Data to Monitor Health Based on Movement
Jul 19 - What Young-onset Parkinson’s Can Look Like
Jul 7 - Parkinson’s Patients Have a Higher Risk of Developing Melanoma — and Vice Versa, Study Finds
Jun 27 - The rogue protein behind Parkinson’s disease may also protect your gut
Jun 26 - Do Statins Increase Risk of Parkinson’s Disease? Some Researchers Think So
Jun 22 - A Confused Immune System Could Be Behind Parkinson's Disease
Jun 21 - Predicting cognitive deficits in people with Parkinson’s disease
Jun 20 - Gym offers classes in noncontact boxing for Parkinson’s patients
Jun 19 - Human Limitations Could Prevent Us From Advancing in Science. AI Could Help.
Jun 13 - Brain Cell Transplants Are Being Tested Once Again For Parkinson's
Jun 12 - Smell Test May Sniff Out Oncoming Parkinson's and Alzheimer's
Jun 8 - Smartphones Track Motor Function in Parkinson's Disease
Jun 8 - GKC Enrolls First Patient in Personal KinetiGraph Trial as Part of NPF’s Parkinson’s Outcomes Project
Jun 8 - Low-fat dairy intake may raise Parkinson's risk
Jun 6 - Patient Voices: Parkinson's Disease
Jun 1 - World-First Trials Have Been Launched to Treat Parkinson's And Blindness With Embryonic Stem Cells
Jun 1 - LIFE Shared This Remarkable Parkinson's Disease Story in 1959.
May 24 - Survival Rates Differ Widely in Parkinson's, MSA, Lewy Bodies
May 22 - Discovery may offer hope to Parkinson's disease patients
May 15 - Study offers answers on life expectancy for people with Parkinson's disease, Lewy body dementia