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Study finds how brain protein's virus-like structure help define cancer-induced memory loss

ANI Feb 01, 2024

In a rare but significant complication of cancer, the body's immune system can begin attacking the brain, resulting in rapid-onset memory loss and cognitive impairment. What precipitated this unexpected biological civil war was mostly unknown.

Researchers at the University of Utah Health have discovered that some cancers can produce a protein that resembles a virus, triggering an out-of-control immune response that may harm brain cells. The findings were published in Cell.

Jason Shepherd, PhD, associate professor of neurobiology at the University of Utah Health and the last author of the study, explains that the swift escalation of symptoms--which can include memory and behavioural changes, loss of coordination, and even seizures--is a hallmark of the disease, called anti-Ma2 paraneoplastic neurological syndrome.

The disease is one of a group of cancer-related neurological syndromes that occur in less than one in 10,000 people with cancer. The precise symptoms of these diseases vary, but all involve rapid immune reactions against the nervous system. "The symptoms come in quickly and can be quite debilitating," Shepherd said.

"This fascinating research illustrates how tumour cells can manipulate their environment," says Neli Ulrich, PhD, executive director of the Comprehensive Cancer Center at Huntsman Cancer Institute at the University of Utah and a Jon M. and Karen Huntsman Presidential Professor in Cancer Research at the U.

"We hope that this innovative transdisciplinary research will positively impact both the lives of cancer patients and of those who experience neurological symptoms."

Stacey L. Clardy, M.D., PhD, a neurologist at U of U Health and a co-author on the study, adds, "Most patients begin to experience these unusual neurologic symptoms before they even know they have cancer."

These rapid-onset symptoms are the result of the immune system suddenly starting to target specific proteins that are found in the brain.

Scientists knew that this flare of immunity often targets a protein called PNMA2. But nobody knew why PNMA2 provokes such a strong immune response, which left researchers at a loss for ways to prevent it.

"We do not understand what is happening at the cellular or molecular level to cause the syndrome," Clardy says, "and understanding the mechanism of disease is crucial to developing better treatments."

To figure out how PNMA2 kickstarts an immune reaction, Junjie Xu, a graduate researcher in neurobiology at U of U Health and the 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 had spontaneously self-organised into 12-sided complexes that resembled the geometric protein shells of some viruses.

One of the immune system's healthy functions is to attack viruses, and PNMA2's virus-like structure makes it particularly prone to being targeted as well, the researchers found. In fact, in an experimental model, the immune system only attacked the PNMA2 protein when it was assembled into virus-like complexes.

The location of PNMA2 in the body is also a crucial piece of the puzzle, the scientists found. "This protein normally is only expressed in the brain, in neurons," Xu says, "but some cancer cells can express it, which can trigger an immune response."

As long as PNMA2 stays in the brain, the immune system won't react to it. But rarely, a tumour elsewhere in the body will start producing PNMA2 protein. And when the immune system detects PNMA2 protein outside the brain, it reacts like it would to any foreign invader.

The immune system makes antibodies that bind to the unfamiliar substance, and those antibodies direct immune cells to attack.

But, once activated, the immune system doesn't just attack the PNMA2 produced by the cancer. It also targets the parts of the brain that produce PNMA2 normally, including regions involved in memory, learning, and movement.

The brain normally has a degree of protection from the immune system, but cancer weakens that barrier, leaving the brain especially vulnerable to this immune onslaught.

In future work, the researchers aim to figure out which aspect of the immune response leads to patients' rapid cognitive decline--the antibodies themselves, immune cells making their way into the brain, or some combination of the two.

Shepherd says that understanding how the immune system causes neurological symptoms may help scientists design targeted treatments.

"If we show that PNMA2 antibodies are the culprit that drives the neurological symptoms, you could devise a way to block those antibodies from getting into the brain or mop them up with something as a treatment. If you can alleviate some of those neurological symptoms, it really would be huge."

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