Study Offers Evidence That Spongiform Brain Diseases Are Caused By Aberrant Protein

Scientists have determined how a normal protein can be converted into a prion, an infectious agent that causes fatal brain diseases in humans and mammals.

The finding, in mice, is expected to advance the understanding of transmissible spongiform encephalopathies, or TSEs, a family of neurodegenerative diseases that include Creutzfeldt-Jakob Disease, kuru and fatal familial insomnia in humans, scrapie in sheep, and bovine spongiform encephalopathy in cattle, also known as “mad cow disease.”

“This study provides the strongest evidence yet to prove the prion hypothesis,” said Jiyan Ma, associate professor of molecular and cellular biochemistry at Ohio State University and senior author of the study. “It also offers important insights into the molecular mechanism and potential therapeutic targets for these diseases.”

The study is in press in the journal Science and appears online as a Science Express report on Jan. 28, 2010.

In 1982, the concept of a prion was introduced as an improperly folded protein that is able to recruit other normal proteins to take on those same characteristics, leading to widespread damage in the brain. However, lingering doubt remained among some investigators that a protein – instead of pathogens like viruses – is actually the infectious agent for these brain diseases.

The skepticism related to unsatisfactory results of creating an infectious prion with recombinant prion protein, a protein created artificially in bacterial cells, which many consider the “holy grail” of the prion field. With this work, Ma and his colleagues were successful in using recombinant protein to generate a prion.

Using a recombinant mouse prion protein, known as PrP, the team discovered that the protein’s interaction with lipids, the main structural component of a cell membrane, leads to its change in conformation, or misfolding of the protein.

The newly formed recombinant prion made mice sick within 130 days after injection into the brain, and those brain tissues from the sick mice infected a second group of mice as well, thus proving the recombinant prion’s serial transmissibility.

“The major thing we showed in this study is that the infectious agent in these diseases is truly a misfolded protein. We folded recombinant mouse prion protein into its normal shape, then converted it into a different conformation and showed that when it infected an animal, it caused full-blown prion disease, with all of the characteristics,” Ma said. ...

Scientists have determined how a normal protein can be converted into a prion, an infectious agent that causes fatal brain diseases in humans and mammals.

The finding, in mice, is expected to advance the understanding of transmissible spongiform encephalopathies, or TSEs, a family of neurodegenerative diseases that include Creutzfeldt-Jakob Disease, kuru and fatal familial insomnia in humans, scrapie in sheep, and bovine spongiform encephalopathy in cattle, also known as “mad cow disease.”

“This study provides the strongest evidence yet to prove the prion hypothesis,” said Jiyan Ma, associate professor of molecular and cellular biochemistry at Ohio State University and senior author of the study. “It also offers important insights into the molecular mechanism and potential therapeutic targets for these diseases.”

The study is in press in the journal Science and appears online as a Science Express report on Jan. 28, 2010.

In 1982, the concept of a prion was introduced as an improperly folded protein that is able to recruit other normal proteins to take on those same characteristics, leading to widespread damage in the brain. However, lingering doubt remained among some investigators that a protein – instead of pathogens like viruses – is actually the infectious agent for these brain diseases.

The skepticism related to unsatisfactory results of creating an infectious prion with recombinant prion protein, a protein created artificially in bacterial cells, which many consider the “holy grail” of the prion field. With this work, Ma and his colleagues were successful in using recombinant protein to generate a prion.

Using a recombinant mouse prion protein, known as PrP, the team discovered that the protein’s interaction with lipids, the main structural component of a cell membrane, leads to its change in conformation, or misfolding of the protein.

The newly formed recombinant prion made mice sick within 130 days after injection into the brain, and those brain tissues from the sick mice infected a second group of mice as well, thus proving the recombinant prion’s serial transmissibility.

“The major thing we showed in this study is that the infectious agent in these diseases is truly a misfolded protein. We folded recombinant mouse prion protein into its normal shape, then converted it into a different conformation and showed that when it infected an animal, it caused full-blown prion disease, with all of the characteristics,” Ma said. ...

via Study Offers Evidence That Spongiform Brain Diseases Are Caused By Aberrant Protein.