PNMA2 Forms Immunogenic Non-Enveloped Virus-Like Capsids Associated with Paraneoplastic Neurological Syndrome

For people with a rare cancer-associated condition called paraneoplastic syndrome, sudden memory loss, loss of coordination, or other neurological symptoms are often the first sign that a tumor is growing somewhere in the body. The symptoms are caused by the immune system's response to it. It turns out that some tumors produce brain proteins. As the immune system learns to recognize and destroy tumor cells, it can also begin to target healthy neurons. This is because neurons naturally produce molecules that aren't found on healthy cells elsewhere in the body. It has remained a mystery why only specific brain proteins made by neurons cause paraneoplastic syndromes. In the lab of U of U Health neurobiologist Jason Shepherd, PhD, researchers are studying a protein called PNMA2 that is normally expressed in the brain but associated with paraneoplastic syndromes. They have found that PNMA2 molecules are released from both tumors and brain cells. In both cases, the proteins assemble into a larger structure that resembles similar structures formed by viruses. Graduate student Junjie Xue found that injecting PNMA2 proteins into mice provoked a particularly strong immune reaction-but only when the proteins assembled into the virus-like structure. Strikingly, the mice developed deficits in learning and memory that resembled the neurological symptoms experienced by paraneoplastic patients. By figuring out exactly how and why paraneoplastic syndrome causes the immune system to attack the brain, Shepherd and his team hope to uncover potential treatment strategies.