Virus-Like Brain Protein May Explain Cancer-Induced Memory Loss

Some tumors can produce virus-like proteins that kick-start out-of-control immune reactions, according to a new study from University of Utah researchers. These rare cancer complications can lead to memory loss and cognitive deficits caused by the immune system attacking the brain.

Rare cancer complications

Cancer patients can sometimes experience a rare condition called paraneoplastic syndrome caused by their underlying tumor. This is where the immune system – in an attempt to fight the cancer – mistakenly attacks healthy cells producing normal proteins elsewhere in the body.

These are rare complications that affect 8–20% of cancer patients and typically lead to poor patient outcomes.

One of these conditions – anti-MA2 paraneoplastic syndrome – occurs when the immune system produces antibodies against PNMA2 proteins. These are found at high levels in the nervous system, meaning the condition has a poor prognosis and can cause coordination issues, memory problems and difficulty walking.

Until now, it was unclear why PNMA2 provoked such a strong response. But uncovering the underlying cause could be key to developing ways to prevent or treat the disease.

The research team – led by Dr. Jason Shepherd, an associate professor in the Department of Neurobiology at the University of Utah – found that PNMA2 proteins assembled into virus-like structures that kick-started the damaging immune response. The study is published in Cell.

Proteins assemble into virus-like structures

Advanced microscopy revealed that PNMA2 proteins had self-organized into 12-sided complexes. These structures, the researchers say, have a striking similarity to the geometric protein shells – or capsids – that encapsulate some types of viruses.

“Based on this, we hypothesized that PNMA proteins could form virus-like capsids, and this is why they trigger the immune system,” Shepherd explained, speaking to Technology Networks.

The immune system seeks out viruses to protect the body’s tissues, so PNMA2’s ability to form virus-like structures could make it an attractive target for the immune system. It is usually only expressed in the nervous system but can be expressed by some cancers, triggering paraneoplastic syndromes by attacking PNMA2 in the brain.

The brain’s usual protection from the immune system, the blood–brain barrier, is weakened in cancer, meaning the brain is particularly susceptible. PNMA2-producing regions of the brain include those responsible for memory, learning and movement, leading to the rapid-onset neurological symptoms experienced by patients.

Shedding light on the immune response and cognitive decline

Though promising, the study's results are limited due to their use of mouse models. Further studies are required to determine whether the same is true in humans.

“The main future directions include determining the normal function of PNMA2 in the brain and determining whether autoantibodies generated to PNMA2 can actually interfere with this normal function,” said Shepherd. “We also plan on doing tumor studies to model human disease in mice.”

“Precisely how PNMA2 capsids trigger the immune response will require further in-depth studies and the development of more chronic models, such as tumor implants, may be required to fully recapitulate human neuropathology and symptoms,” he added.

Reference: Xu J, Erlendsson S, Singh M, et al. PNMA2 forms immunogenic non-enveloped virus-like capsids associated with paraneoplastic neurological syndrome. Cell. 2024. doi: 10.1016/j.cell.2024.01.009

Dr. Jason Shepherd was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.

About the interviewee:

Jason Shepherd is an associate professor in the Department of Neurobiology at the University of Utah, where he also holds the Jon M. Huntsman Presidential Chair. His research focuses on understanding neuronal networks and information storage, and how these can influence neurological disorders. Jason holds a BSc from the University of Otago and a PhD from the Johns Hopkins School of Medicine and underwent postdoctoral training at the Massachusetts Institute of Technology (MIT).