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Research Boosts New Theory About How Parkinsonís Starts
- Jun 26 2014
An emerging theory about the causes of Parkinson’s disease (PD) suggests that toxic clumps of the protein alpha-synuclein may spread the disease from cell to cell. Research published in the March issue of Annals of Neurology provides the evidence to support this idea in animal studies.
The role of the normal, healthy alpha-synuclein is not fully established, but scientists have been studying its relationship to Parkinson’s disease for more than a decade. Scientists know that in Parkinson’s disease, the proteins form into abnormal (or toxic) clumps called Lewy bodies, in the brain cells that help direct the body’s movement. These clumps, which are visible only on examining the brain at autopsy, are the hallmark of PD in the brain. Studies in mice have pointed to the idea that the toxic clumps of alpha-synuclein may spread from one region of the brain to another, and even cause normal alpha-synuclein to change shape and form Lewy bodies.
Researchers led by Miquel Vila, M.D., Ph.D., at the Vall d’Hebron Research Institute – Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain, carried out experiments to test this further. The scientists extracted both normal alpha-synuclein and clumps of abnormal (or toxic) alpha-synuclein from brain tissue obtained after autopsy from people with PD. Toxic alpha-synuclein was injected into one group of mice, and normal alpha-synuclein was injected in the other group in the brain region affected by PD. The experiment was repeated in macaque monkeys, whose brains are much more similar to human brains than are those of mice.
- Up until four weeks after the injections, scientists still found evidence of the human alpha-synuclein in mice injected with toxic form of the protein. After that point, they could no longer find human alpha-synuclein, but observed that the mice’s own alpha-synuclein had been converted to the toxic form.
- Four months after receiving toxic alpha-synuclein, the brains of the same group of mice began showing nerve cell death similar to what happens in people with PD, progressively worsening for up to 17 months – the duration of the study.
- Two monkeys receiving toxic alpha-synuclein lost about a third of their dopamine neurons in a manner consistent with Parkinson’s disease.
- In the animals injected with only normal alpha-synuclein, scientists did not see any neurodegeneration. Instead, neurons remained healthy.
What Does It Mean?
Scientists have been trying to understand how PD progresses for many years. Recently, the hypothesis that toxic alpha-synuclein spreads from affected cells to healthy ones, has drawn much attention. This research shows for the first time in monkeys (whose brains are much more similar to humans than are rodents) that the toxic form of alpha-synuclein can spread, and trigger the process of nerve cell death in the part of the brain affected by PD.
This provides important support for the hypothesis that toxic alpha-synuclein can be transferred from sick cells to healthy ones and hence explain the progressive nature of PD. However, the authors caution that they have not explicitly shown that it is the toxic alpha-synuclein (rather than, for example, a powerful inflammatory response) that has triggered the Parkinson’s-like cell death in the brains of these animals.
Despite these concerns, the research community is very enthusiastic about the results of this study. Jeffrey Kordower, Ph.D., a lead scientist at PDF’s Research Center at Rush University who was one of the first to discover this process praised this study in an editorial written for the May 27 online edition of Movement Disorders. He noted that because this research was able to more faithfully replicate the progression of PD, it is likely to significantly change how scientists do PD research in the future and will have important implications for testing new, neuroprotective PD therapies (therapies that would protect neurons). This is because a major challenge in PD research is the lack of animal models that imitate the disease biology.
If further research continues to show that this new method of creating model animals for PD research is fruitful (by “infecting” animals with toxic human alpha-synuclein), then such animals may serve as a more realistic model in which to test potential treatments and speed their pathway to the clinic, to help people who live with Parkinson’s disease.
Reference: Recasens A, Dehay B, Bové J, Carballo-Carbajal I, Dovero S, Pérez-Villalba A, Fernagut P-O, Blesa J, Parent A, Perier C, Fariñas I, Obeso JA, Bezard E, Vila M (2014) Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 75:351–362. DOI: 10.1002/ana.24066 http://dx.doi.org/10.1002/ana.24066
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Source Date: Jun 18 2014