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Misfolded Protein Infects Cells with Parkinsonís Disease in Healthy Mice

For the first time, scientists have shown that a protein can cause the spread of Parkinson’s disease (PD) pathology from cell to cell in the brains of otherwise healthy mice. This study, published in the November 16, 2012 issue of Science, shows an animal model that closely mimics the progression of PD in people, which may help scientists develop more effective treatments.

In brain cells (neurons) of people with PD, the α-synuclein protein becomes misfolded, or damaged. It forms clumps, called Lewy bodies. Until now, scientists were unable to prove that the misfolded protein caused the death of neurons and the subsequent loss of dopamine that leads to symptoms of Parkinson’s disease.

Scientists think it is possible that damaged α-synuclein protein may start in one place in the brain and then spread cell-to-cell, infecting healthy cells as it spreads. If this theory 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.

Researchers led by Virginia M.-Y. Lee, Ph.D., at the University of Pennsylvania Perelman School of Medicine developed a new animal model that allowed them to study this process in detail. The researchers injected laboratory-made clumps of α-synuclein protein, known as α-synuclein fibrils, into the brains of healthy mice and observed changes in the brain over three months.

Results

  • One month after the injection of α-synuclein fibrils in a single location in the brain, Lewy bodies had formed in neurons at the injection site, as well as in neurons connected to these cells. At three and six months after the injection, the Lewy bodies had spread further, reaching regions of the brain typically affected in people with PD.
  • As the Lewy bodies spread in the brain over time, the mice lost more and more dopamine-producing neurons on the side of the brain that had been injected. Six months after the injection, half of dopamine-producing neurons on that side of the brain were gone, meaning, dopamine levels in the brain decreased.
  • The injected mice showed some motor symptoms similar to those of PD in people, such as decreased motor strength and coordination.

What Does It Mean?

Even though it is well known that Parkinson’s disease is a progressive disease, scientists know very little about the biology of disease progression. This group of researchers from the University of Pennsylvania hypothesizes that PD progresses because misfolded proteins are transferred from affected cells to healthy cells.

They and other researchers have demonstrated their theory in cell cultures and in mice carrying PD genetic mutations. This is the first time that they demonstrate the hypothesis in healthy animals. These mice more closely resemble people with the sporadic, or non-inherited, form of PD, which accounts for most cases of PD. This study provides strong support for the so-called “prion hypothesis” of PD.

This new animal model should enable researchers to better understand the cause-and-effect relationship between α-synuclein protein and the death of dopamine-producing neurons, and the progression of PD. In addition, the method used by researchers could help scientists test new treatments to slow or halt PD progression. 

Prion-like proteins or proteins that clump and aggregate together have been hypothesized to play a role 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:
Luk, K., Kehm, V., Carroll, J., Zhang, B., O'Brien, P., Trojanowski, J. Q., & Lee, V. M.-Y. (2012). Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science (New York, NY), 338(6109), 949–953. doi:10.1126/science.1227157

Source Date: Dec 12 2012