Issue Date: September 7, 2015 | Web Date: September 2, 2015
Another Neurodegenerative Disease Linked To Prion Mechanism
A study concludes that the brain protein α-synuclein causes the rare, Parkinson’s-like disease called multiple system atrophy (MSA) by acting like a prion, the misbehaving type of protein infamously linked to mad cow disease.
The team says the results are the most definitive demonstration to date that proteins involved in many neurodegenerative disorders, such as Alzheimer’s and Parkinson’s, exhibit prionlike behavior: They can misfold into shapes that then coax others to do the same, leading to protein aggregation that forms neurotoxic clumps.
The new findings and their implications are compelling, says Neil R. Cashman, a neurologist at the University of British Columbia, who was not involved in the study. “If there is a prionlike component in these diseases, which it looks like there is, then understanding the process and targeting the process opens the door for novel therapeutics.”
Over the past several years, neurobiologists have shown that proteins, such as Alzheimer’s amyloid-β and Parkinson’s α-synuclein, can propagate prionlike misfolding in the brains of mice. But none of these experiments demonstrated that this propagation led to neurodegeneration in the animals.
A team led by Stanley B. Prusiner and Kurt Giles of the University of California, San Francisco, now report that α-synuclein associated with MSA can do just that in mice. In 1997, Prusiner won the Nobel Prize in Physiology or Medicine for discovering prions a decade earlier.
The scientists collected brain samples from 14 deceased MSA human patients and injected dilutions of the homogenized tissue into the brains of mice genetically engineered to express the human version of α-synuclein. The team added a mutation to the α-synuclein gene to increase the protein’s propensity to misfold.
“After about four months, all the mice died,” Giles says. When the researchers analyzed the animals’ brains, they found deposits of aggregated α-synuclein (Proc. Natl. Acad. Sci. USA 2015, DOI: 10.1073/pnas.1514475112).
To further test the prionlike behavior of α-synuclein, the scientists injected brain tissue from the dead mice into other mice. Again, the animals all died within about four months, and their brains had accumulated α-synuclein clumps. This ability to pass the disease from animal to animal through brain tissue is a hallmark of prion propagation.
But transmission into the same engineered mice didn’t work when the researchers used brain samples from human Parkinson’s patients, even though both diseases involve α-synuclein. This observation suggests that α-synuclein in MSA may adopt a different misfolded conformation from the one it assumes in Parkinson’s. Classical prions also exhibit these so-called strains, in which the same protein can have different disease-causing abilities.
The findings from this study and previous ones “give us a new concept for doing drug discovery,” Giles says. Researchers have already started to develop antibodies and small molecules that can slow the aggregation of classical prions in the brain. A similar approach could work for other neurodegenerative disease, he says.
- Chemical & Engineering News
- ISSN 0009-2347
- Copyright © American Chemical Society