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New Animal Model for Parkinsonís Strengthens Role for Protein Spreading
- Jul 10 2012
For the first time, scientists have shown in an animal model of Parkinson’s disease (PD) that α-synuclein protein can spread from diseased to healthy neurons and stimulate α-synuclein aggregation in the healthy cells. This study, published on June 21, 2012 in PLoS ONE, supports a potential role for the cell-to-cell transfer of α-synuclein proteins in PD progression.
Parkinson’s disease arises when misfolded α-synuclein protein forms toxic clumps, called Lewy bodies, in brain cells. The affected neurons eventually die, reducing dopamine production in the brain and causing the classic symptoms of PD.
Previous studies demonstrated that when people received experimental implants of dopamine neurons, their autopsies 10-22 years later revealed that some of the implanted, “healthy” neurons now contained Lewy bodies — the marker of PD. Scientists speculated that damaged α-synuclein protein, although not infectious from person to person, may be able to start in one place in the body and then spread from cell to cell. Damaged or misfolded α-synuclein may “seed” protein clumps in healthy cells, causing the normal α-synuclein in these cells to misfold and clump together, or aggregate. If this hypothesis is correct, then α-synuclein belongs to a class of infectious proteins known as prions. Other prions cause neurological diseases such as mad cow disease in cattle and Creutzfeldt-Jakob disease in humans.
Experiments in cells and animals have provided evidence for certain aspects of the hypothesis, but until now, scientists haven’t been able to observe the entire sequence of events. Researchers led by Elodie Angot, Ph.D., at Lund University, in Sweden, under the direction of Patrik Brundin, M.D., Ph.D., now at Michigan State University’s Van Andel Research Institute, devised a new animal model that allowed them to study this process in detail. In particular, they then grafted embryonic rat neurons into the brains of adult rats that were engineered to make excessive amounts of the human form of α-synuclein.
- The researchers detected frequent transfer of α-synuclein from the host rats' brain neurons to the transplanted neurons. The frequency of the transfer generally increased with time after new neurons were grafted.
- The transfer of α-synuclein between cells appeared to occur via a specific process called endocytosis, where cells take up or “drink” small amounts of fluid and the small particles it contains from outside the cell.
- Once inside the transplanted neurons, the transplanted human α-synuclein became surrounded by a larger amount of rat α-synuclein. This observation suggests that human α-synuclein seeded the aggregation of rat α-synuclein.
What Does It Mean?
The most challenging characteristic of PD is its progressive nature. To date, scientists do not understand what causes PD to progress, and therefore, there are no available treatments to prevent or stop the disease. However, for the first time in an animal model, researchers observed the transfer of α-synuclein into transplanted neurons and the subsequent “seeding” of α-synuclein aggregates in the healthy recipient neurons. This study provides perhaps the most compelling evidence to date to support the so-called “prion hypothesis” of PD, which may provide one possible explanation of how the disease advances.
This new animal model should enable researchers to better understand how Lewy bodies form and may enable researchers to study PD progression and test for interventions that may halt it. For example, scientists might be able to use these rats to identify or test drugs that interfere with the cell-to-cell transfer of α-synuclein.
Prion-like proteins or proteins that clump and aggregate together have been detected in several common neurological diseases in addition to PD, including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). If the spreading from cell-to-cell of prion-like proteins indeed proves to be a common mechanism underlying multiple neurodegenerative diseases, then similar strategies might be used to slow the progression of all these diseases.
Reference: Angot, E., Steiner, J. A., Lema Tomé, C. M., Ekström, P., Mattsson, B., Björklund, A., & Brundin, P. (2012). Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo. PloS one, 7(6), e39465. doi:10.1371/journal.pone.0039465
Source Date: Jul 10 2012