Important Perk

James Devitt and Barbara K. Kennedy
August 09, 2012

Researchers have identified in mice a protein that is necessary for maintaining behavioral flexibility, the ability to adapt to changing circumstances. Their findings may offer new insights for addressing such human afflictions as autism and schizophrenia, in which this ability is significantly impaired.

The protein, named PERK, is a vital component in protein synthesis. “A major obstacle to investigating the role of the PERK protein in regulating behavior is that many other body functions also are dependent upon this protein,” notes Douglas Cavener, department head and professor of biology at Penn State and a co-author of the research paper describing the discovery.

man sitting next to a counter in his laboratory

Douglas Cavener, professor of biology

“To overcome this problem, my lab developed a mouse strain that allows us to mutate the PERK gene specifically in a single organ or cell type, while the PERK gene remains normal in other parts of the body."

Specifically, Cavener and his colleagues developed a strain in which the PERK gene—and therefore the PERK protein—was missing only from the forebrain. “This allowed us to investigate the function of the PERK protein in the brain without the severe complications of other dysfunctions in the body,” Cavener explains.

In one experiment, normal and PERK-deficient mice were asked to navigate a water maze. Both learned to complete this task. However, when the maze's platform was moved to another location, those lacking the PERK in their forebrains were unable to locate it, or took significantly more time to do so.

In a second test, both normal and mutant mice heard an audible tone followed by a mild foot shock. All of the mice developed a normal fear response—freezing at the tone in anticipation of the shock. But when the researchers removed the shock, leaving only the tone, the normal mice adjusted their responses while the mutant mice continued to respond as if they expected a foot shock to follow.

To further support their conclusions, the researchers conducted postmortem analyses of human cells, comparing cells taken from the frontal cortexes of people without schizophrenia with similar cells from schizophrenic patients. The samples from the non-schizophrenic group showed normal levels of PERK protein, they report, while those from the schizophrenic patients had significantly reduced levels of the protein.

“A rapidly expanding list of neurological disorders and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Fragile X syndrome, already have been linked to aberrant protein synthesis,” explains Eric Klann, a professor at New York University and one of the study's co-authors. “Our results show the significance of PERK in maintaining behavioral flexibility and how its absence might be associated with schizophrenia.”

“Further studies clarifying the specific role of PERK-regulated protein synthesis in the brain may provide new avenues to tackle such widespread and often debilitating neurological disorders.”

Douglas Cavener, Ph.D., is department head and professor of biology at Penn State, Eric Klann, Ph.D., is a professor in New York University’s Center for Neural Science. The study’s other co-authors are Mimi Trinh and Hanoch Kaphzan, both formerly of NYU; Ronald Wek, of the Indiana University School of Medicine; and Philippe Pierre of France's Université de la Méditerranée.

The paper that resulted from this work was published in May in the journal Cell Reports. Funding came from the National Institutes of Health, the FRAXA Research Foundation, and the Bill and Melinda Gates Foundation.

Last Updated August 09, 2012