Who knew? Arc neuroplasticity gene shares common denominator with viruses

Researchers from two universities have made a fortuitous discovery—genes may act like viruses and transfer genetic material to neurons.

The Arc gene, which plays a critical role in learning and memory, may be capable of spreading its genetic material from neuron to neuron using the same process used by viruses, according to researchers from the University of Utah, Salt Lake City, UT, and the University Massachusetts Medical School, Worcester, MA. Results from both studies are published in Cell.

“This work is a great example of the importance of basic neuroscience research,” said Edmund Talley, PhD, program director, National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, Bethesda, MD. “What began as an effort to examine the behavior of a gene involved in memory and implicated in neurological disorders such as Alzheimer’s disease has unexpectedly led to the discovery of an entirely new process, which neurons may use to send genetic information to one another.”

Previously, researchers had found similarities between the Arc protein and proteins found in certain viruses such as HIV. What was not clear, however, was how or if these similarities influenced the behavior of the Arc protein.

At the University of Utah, researchers introduced the Arc gene into bacterial cells. When the cells made the Arc protein, the material clumped into a form similar to a viral capsid—a shell that holds the genetic information for a specific virus. The unexpectedly discovered Arc capsids seemed to be the same as viral capsids in physical structure, behavior, and other properties.

“Beforehand, if I had said to any neuroscientist that this gene sort of acts like a virus, they would have laughed at me,” said Jason Shepherd, PhD, assistant professor, University of Utah. “We knew this was going to take us in a completely new direction.”

And while University of Utah researchers were studying bacterial cells, researchers at the University of Massachusetts led by Vivian Budnik, PhD, professor, were exploring extracellular vesicles in fruit flies. They found that the motor neurons in control of fly muscles release vesicles with high concentrations of the Arc gene’s messenger RNA (mRNA).

Both sets of researchers also found evidence that Arc capsids contain Arc mRNA, and these capsids are released from neurons inside those vesicles. The more active neurons became, the more vesicles they released.

Results from both groups suggest that Arc capsids act similarly to viruses by delivering mRNA to nearby cells. Mouse neurons without the Arc gene were grown in petri dishes filled with Arc-containing vesicles or Arc capsids alone. The neurons without Arc took in the vesicles and capsids and used the Arc mRNA they contained to produce the Arc protein. And like neurons with the Arc gene, these cells produced more Arc with increasing electrical activity.

Researchers at the University of Massachusetts also showed that Arc mRNA and capsids travel in only one direction between fly cells, from motor neurons to the muscles, and that the Arc protein binds to a specific part of the Arc mRNA molecule—the untranslated region—which is not used to make the Arc protein. Further, flies lacking the Arc gene formed fewer motor neuron connections than normal flies. When motor neurons are more active, normal flies create more of these connections, while flies without the Arc gene did not.

Both research teams plan to investigate why cells use this virus-like strategy to shuttle Arc mRNA between cells, and whether this system enables the toxic proteins responsible for Alzheimer’s disease to spread in the brain.

The hope is that their research will help elucidate further the development of neurologic diseases.

In addition, the Arc capsids may be useful for genetic engineering and gene therapy. Viruses are currently used in both to introduce new genetic instructions into cells. Side effects can occur, due to immune system attack of these viruses. But because Arc proteins are autologous, they may not trigger an immune response and be more successful at delivering genes for gene therapy.

“This research highlights the fact that we often don’t know where the cool discoveries are going to come from,” Dr. Shepherd said. “We need to follow where the science takes us.”

Dr. Shepherd’s work was supported by the NINDS (NS076364), the NIH’s National Institute of Mental Health (MH112766), and the NIH’s National Institute of General Medical Sciences (GM77582 and GM112972). Dr. Budnik’s and Dr. Thomson’s research was supported by the National Institute of Mental Health (MH070000).