Unveiling the mystery behind rapid memory loss in cancer patients

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In a rare but serious complication of cancer, the body’s own immune system can begin to attack the brain, causing rapid memory loss and cognitive deficits. What triggered this sudden biological civil war was largely unknown.

Now, researchers at the University of Utah Health have found that some tumors can release a protein that looks like a virus, triggering an out-of-control immune response that can damage brain cells.

Their findings are published cell on January 31, 2024.

A rapid immune attack

Jason Shepherd, PhD, associate professor of neurobiology at University of Utah Health and last author of the study, explained that a rapid increase in symptoms—which can include memory and behavioral changes, loss of coordination, and even seizures—; A feature of the disease is called anti-Ma2 paraneoplastic neurological syndrome. The disease is a group of cancer-related neurological syndromes that affect less than one in 10,000 people with cancer. The specific symptoms of these diseases vary, but all involve a rapid immune response against the nervous system. “Symptoms come on quickly and can be quite debilitating,” Shepherd says.

This fascinating study explains how tumor cells can manipulate their environment. We hope that this innovative transdisciplinary research will positively impact the lives of both cancer patients and those experiencing neurological symptoms.”

Nellie Ulrich, PhD, is executive director of the Comprehensive Cancer Center at the Huntsman Cancer Institute at the University of Utah and the John M. and Karen Huntsman Presidential Professor in Cancer Research in the United States.

Stacey L. Clardy, MD, PhD, a neurologist at U of U Health and a co-author of the study, added, “Most patients start experiencing these unusual neurological symptoms before they know they have cancer.”

These rapid-onset symptoms result from the immune system suddenly starting to target specific proteins found in the brain. Scientists knew that these flares of immunity often target a protein called PNMA2. But no one knew why PNMA2 provoked such a strong immune response, leaving researchers at a loss for ways to prevent it. “We don’t understand what’s actually happening at the cellular or molecular level to cause the syndrome,” Clardy said, “and understanding the disease process is crucial to developing better treatments.”

Looks like a virus

To figure out how PNMA2 initiates an immune response, Junji Xu, a graduate researcher in neurobiology at U of U Health and lead author of the study, examined the protein’s structure using advanced microscopy. When he saw the first clear image of the protein, he was “so, so excited,” Xu said. Multiple PNMA2 proteins spontaneously self-assemble into 12-sided complexes that bear a striking resemblance to the geometric protein shells of some viruses.

One of the healthy functions of the immune system is to attack viruses, and PNMA2’s virus-like structure makes it especially vulnerable to being targeted, the researchers found. In fact, in mice experiments, the immune system only attacked the PNMA2 protein when it was assembled into a virus-like complex.

Wrong place, wrong time

PNMA2’s location in the body is also an important piece of the puzzle, the scientists found. “This protein is normally only expressed in the brain, in neurons,” Xu said, “but some cancer cells can express it, which can trigger an immune response.”

As long as PNMA2 is in the brain, the immune system will not react to it. But rarely, tumors elsewhere in the body will start producing PNMA2 protein. And when the immune system detects the PNMA2 protein outside the brain, it reacts like a foreign invader. The immune system produces antibodies that bind to foreign substances, and those antibodies instruct immune cells to attack.

But, once activated, the immune system doesn’t just attack the PNMA2 produced by the cancer. It also targets areas of the brain that normally make PNMA2, including areas involved in memory, learning and movement. The brain normally has some protection from the immune system, but cancer weakens that barrier, making the brain especially vulnerable to these immune attacks.

In future work, the researchers aim to determine which aspects of the immune system lead to faster cognitive decline in patients—; Antibodies themselves, immune cells make their way to the brain, or some combination of the two.

Understanding how the immune system causes neurological symptoms could help scientists design targeted treatments, Shepherd said. “If we show that the PNMA2 antibodies are the cultures that are really driving the neurological symptoms, you can develop ways to prevent those antibodies from getting into the brain or to remove them with something as a treatment… If you can alleviate some of these neurological symptoms,” it’s really would be huge.”


Journal Reference:

Xu, J., etc (2024) PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndromes.. cell doi.org/10.1016/j.cell.2024.01.009.

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