Establishing a direct link between Lewy bodies and Parkinson’s disease
November 15, 2012 § Leave a comment
What role does alpha-synuclein play in Parkinson’s disease? The protein’s involvement has been controversial because it’s not clear whether buildup of the abnormal version of the protein actually causes the onset of the disease.
But in a paper just out in Science, researchers demonstrated that healthy mice developed the telltale signs of the Parkinson’s disease when their brains were injected with the abnormal protein. This suggests that the buildup of abnormal alpha-synuclein could cause the disease.
Virginia Lee at the University of Pennsylvania Perelman School of Medicine, who spearheaded the research, explains that there has been a lack of evidence to show a direct link between the accumulation of alpha-synuclein in deposits known as Lewy bodies and a loss of dopaminergic neurons. Dopaminergic neurons produce dopamine; the loss of dopamine causes the movement disorder in Parkinson’s patients.
Lee says there haven’t been any animal models that connect Lewy bodies to dopaminergic neuron loss. For example, “transgenic mice overexpressing alpha-synuclein develop Lewy bodies but have no dopaminergic cell loss,” she says. “In our new alpha-synuclein injection model using wild-type, nontransgenic mice, we were able to provide this link of alpha-synuclein–Lewy-body accumulation and dopaminergic cell loss.”
Lee and colleagues decided to take an approach that had been previously used to study prion diseases, in which a misfolded conformation of a protein can corrupt and recruit normal forms of the protein to adopt the misfolded conformation. “The rationale for this particular approach is that, among patients with Alzheimer’s and Parkinson’s, the burden of the disease pathology, such as Lewy bodies and neurofibrillary tangles, increase over time in the brain and appear to correlate with clinical phenotypes,” explains Lee.
The investigators injected synthetic alpha-synuclein fibrils produced from recombinant mouse alpha-synuclein protein into the brains of normal mice. They found that the misfolded alpha-synuclein formed Lewy bodies. The mice progressively lost dopaminergic neurons and developed movement deficits similar to those observed in Parkinson’s disease.
Lee says the work shows a direct link between the formation of Lewy bodies made from alpha-synuclein and loss of dopaminergic neurons, which then leads to the disease pathology. Lee adds the work also provides a new animal model for studying cases of Parkinson’s disease when the disease crops up unexpectedly (as opposed to those cases where there is a family history of the disease and a different disease mechanism may be involved).
Next, Lee says she and her colleagues would like to “use our model for the development of potential therapies for Parkinson’s disease since this model provides new opportunities for the identification of novel targets.” She adds that they would also like to pursue the mechanism by which alpha-synuclein forms Lewy bodies.