Prion Proteins

Corinne Lasmezas, DVM, PhD, and a team of researchers at The Scripps Research Institute’s Department of Infectology, are working to find cures for prion diseases as well as age-related brain disorders. These all are fatal neurodegenerative diseases. Included in this group of neurodegenerative diseases are Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Fronto-Temporal Dementia.

There are no cures, Lasmezas said. “For Alzheimer’s, there are five FDA-approved drugs, but although they can delay the symptoms, they don’t cure the disease.”

However, the Scripps researchers have identified one blocking neuroprotective compound and four suppressing compounds that hold promise.

In humans, Creutzfeldt-Jakob Disease is a rare prion disease that is inherited, can occur for no known reason or through exposure to contaminated products. Kuru is another prion disease. It was found in young men, women and children in a tribe in Papua New Guinea who ate human brain as part of a funerary rite.

In animals, prion diseases include Mad Cow Disease, scrapie found in sheep and goats, and chronic wasting disease found in deer and elk.

Lasmezas, whose work provided the proof that Mad Cow Disease had been transmitted to humans in 1996, explained that there is a similarity in prion diseases and age-related brain disorders – they have types of proteins that misfold.

“Prion diseases are transmissible, but we didn’t know what the infectious agent causing these diseases was. This was an enigma,” Lasmezas said.

“Usually, we get infectious diseases through bacteria or a virus. Sometimes, diseases are caused by parasites or fungi. But none of these diseases were caused by any of these agents.”

Finally, she explained, scientists found dark plaques in brain matter consisting of fibers made of protein. “The infectious agents turned out to be proteins,” and, hence, they were called prions, (proteinaceous infectious particles). Later, Dr. Charles Weissmann, chair of Scripps Department of Infectology, found that the prion proteins were produced in the cells. But, how, the scientists wanted to know, is it possible that a protein, produced by our cells, can be infectious and harmful?

“Every protein has a shape. When a protein changes its shape, it can’t perform its function and it can become harmful. This is what happens in prion diseases. The protein changes shape (misfolds), induces other proteins to change shape, forms chains and then forms plaque. This process is harmful to the brain.”

When a neuron gets sick, she explained, it retracts its extensions, so it can’t communicate anymore. Its overall metabolism slows down and the neuron accumulates junk, which it tries to contain in little pockets, called vacuoles.

“If at this point, we could intervene, we could revert that fate and go back to having healthy neurons. Otherwise, the neuron loses its extensions; it becomes full of vacuoles and dies. Like prion diseases, in most age-related neurodegenerative diseases, proteins (other than the prion protein) also change shape.”

To understand how these misfolded proteins kill the neurons, Lasmezas’ team engineered a normal protein. “We put them on neurons, and they were fine.  If we cooked the protein for 15 minutes, though, the protein changed its shape and started making a chain (oligomers) and if we put that on neurons, it was very toxic.”

Then, the researchers found a method to produce the toxic protein.

They took healthy neurons and put them in a culture. When a normal form of the protein was added to a culture, nothing happened to the neuron. But when they put the toxic form on the neurons, the neurons lost their extensions, became full of vacuoles and died.

Next, the researchers developed a test to find drugs to prevent neuron death in prion disease and Alzheimer’s disease. “We tested a small collection of compounds and through that test, we found a neuroprotective compound.

“Then we repeated the culture experiment using the toxic prion protein, and the neurons started losing extensions and accumulate vacuoles. But when we added the neuroprotective compound, the neurons started resuming their shape in three hours and in two days they were perfectly happy. They grew back their extensions.

“This showed us that we can find neuroprotective compounds that can block the toxic protein and also revert neurons that were going to die. It was a strong signal of hope that we can find cures for those neurodegenerative diseases.”

To make sure, the researchers adopted a second strategy, based on a finding of Scripps Research scientist Charles Weissmann in 1993, that mice that don’t have the prion protein couldn’t be infected by prion disease. “So the elimination of the prion protein is protective against prion disease,” she explained.

“Recently, a researcher at Yale found that not having prion protein protected against Alzheimer disease. The aggressive form of the Alzheimer’s protein only attacks the neuron with the prion protein. We wanted to verify this finding.

“What we did, we took a cell line that expresses a prion protein at its surface and infected it with the destructive toxic Alzheimer’s protein, and the neurons died.

“Then with neurons without the prion protein, we added the toxic Alzheimer’s protein and nothing happened.”

Lasmezas and Weissmann teamed up to develop a screening test to find drugs that eliminate the prion protein from the neuronal surface to cure prion disease and Alzheimer’s.  “At Scripps, we have a great drug discovery platform led by Peter Hodder. There is a robot that can screen a hundred thousand compounds per day.”

“We did a preliminary screening using a drug collection of 1,280 compounds, followed by a whole battery of tests and ended up finding four compounds that suppress the prion protein.”

The researchers now have one neuroprotective compound and four compounds that suppress prion proteins, and they are actively investigating their therapeutic effect in prion and Alzheimer’s disease models.

Equally important, the researchers also have two high throughput screening tests that can be adapted to screen for other neurodegenerative diseases.

AND AS A SIDE NOTE:

In addition to asking Scripps scientist Corinne Lasmezas about toxic prion proteins, the culprit in Mad Cow Disease, let’s ask her to get to the meat of the matter.

What cuts of beef are ok to eat? Lasmezas, whose work provided the proof that Mad Cow Disease had been transmitted to humans in 1996, said these days, any cut is ok. “It was beef brain that caused the disease (brain used to be in sausages, ground meat and even baby food), but that’s prohibited. Brain is not mixed into foods anymore,” she said.

A type of protein that misfolds like prion protein is also the culprit in Alzheimer’s Disease. So, here’s a second quick question for Lasmezas. Is there anything we can do to guard against getting Alzheimer’s?

A healthy lifestyle reduces the risk, she said. “The brain needs energy and you need to have a healthy cardiovascular system to bring the brain oxygen and nutrients.”

The brain needs exercise, too.

“The more you exercise your brain, you make new networks and increase your cognitive reserve. Exercise does influence how the brain ages.”

In addition, Lasmezas drinks green tea. “It has EGCG in it, which has been found to slightly decrease the production of the Alzheimer’s protein,” she said

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