Proteins gone wild

Thirty years ago, Stanley Prusiner had a heretical idea: that proteins, the complex molecules involved in virtually all cell functions, could go bad and set off deadly brain disorders — such as mad cow disease — which, at the time, were thought to be caused by viruses. He called these mutant proteins “prions.”

Fifteen years later, his heresy was recognized with the Nobel Prize in Medicine or Physiology. Today, Prusiner continues to try to understand the molecular basis of prion formation, its possible role in a wide range of neurodegenerative diseases like Parkinson’s and Alzheimer’s and how they can be treated. He shared some of his findings at Freeborn Hall on Friday while delivering the UC Davis Veterinary School’s Robert Dyar Memorial lecture, titled “Football players, soldiers, and Alzheimer’s patients: What do they have in Common? Brain injuries.”

The function of proteins depends largely on the specific ways they fold into three-dimensional structures. When proteins occasionally misfold, quality control mechanisms in the cell usually step in to quickly dispose of them. But under certain conditions which are still not exactly clear, they can morph into forms that are not only highly resistant to destruction, but which can set off a chain of self-propagating mutations in neighboring proteins.

UC Davis Veterinary School professor Philip Kass says this is the kind of scenario once envisioned only in stories like the Andromeda Strain, where a pathogen spreads without the conventional genetic replication mechanisms of DNA or RNA molecules.

“The idea that this could happen is fairly radical,” Kass said. “[Prusiner] took something that sounded like it came from science fiction and showed that it could happen in animals and humans.”

Prusiner, who directs the Institute of Neurodegenerative Diseases at UCSF, believes that prions are implicated in virtually all neurodegenerative diseases, which involve the progressive loss of brain function. He said that the apparent connection between repeated head injuries of the type sustained by football players and soldiers and delayed effects in the form of neurodegeneration years later have given him a new focus for his work in the last several years.

“This is a huge problem and it’s just going to grow and grow and grow,” Prusiner said.

For the most part, the news is bad. There are currently no drugs proven to stop or even slow neurodegenerative diseases, which are on the rise among aging populations worldwide. Prusiner also called claims that the risk of Alzheimer’s can be mitigated by lifestyle choices, like diet, “total nonsense.” Meanwhile, he is behind an ambitious effort to “get to the fundamental degenerative process” in such diseases from his laboratories at UCSF, where he said he is assembling the largest group of chemical biologists in the world to synthesize the molecular arsenal needed to effectively target prions.

This came as welcome news to Nancy Stoltz, who drove from Sacramento to see Prusiner’s talk. Stoltz said she was recently diagnosed with cognitive impairment from a brain injury sustained during an automobile accident.

“It actually hurt my brain to listen to [the lecture],” Stoltz said. “But it was very interesting to hear that he’s trying to do something besides just treat the symptoms. It never occurred to me that you’d try to cure the cause.”

When the good news comes, it will likely be years in the future, given how intractable prion-related diseases have proven. Prusiner said his effort itself is also controversial, since the exact role of prions in diseases such as Alzheimer’s is still disputed.

“What I’m telling you is not generally accepted,” he told the audience. “People have been working in a different paradigm and it’s extremely hard to shift. What we’re seeing is something fascinating, and I see it as a revolution in medicine and biology.”

OYANG TENG can be reached at science@theaggie.org.

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