Schwann cells may trigger NF1 pain before tumors appear, mouse study suggests

Researchers at Cincinnati Children’s have identified a potential new way to relieve chronic pain linked to neurofibromatosis type 1 (NF1), a genetic condition best known for causing tumors to grow along nerves. The new findings suggest that pain in NF1 may begin before tumors appear and may be driven by abnormal signaling from Schwann cells, which normally support and protect nerves. The abnormal signaling produces excess glial cell line–derived neurotrophic factor (GDNF), a protein that can heighten pain signaling.

The work is published in the journal Science Signaling. Namrata G. R. Raut, Ph.D., was the first author, and Michael P. Jankowski, Ph.D., was the corresponding author.

“The work helps explain why many people with NF1 report significant pain even in areas where no tumors are present,” Jankowski says. “Importantly, we also found that blocking MAPK signaling with a MEK inhibitor lowered GDNF levels in Schwann cells and reduced pain-like responses in the mice.”

NF1 affects about one in 3,000 people and can cause a wide range of symptoms, including café-au-lait spots, learning and skeletal problems, plexiform neurofibromas and chronic pain. Although tumor-related pain in NF1 is well recognized, non-tumor pain has remained poorly understood and difficult to treat. The new study focused on that gap.

Using a mouse model in which the NF1 gene was deleted in Schwann cells, the investigators found that those cells were the main source of excess GDNF. The protein acted through a receptor called GFRα1 on pain-sensing nerve fibers, helping drive mechanical hypersensitivity.

The researchers also found that using mirdametinib, a MEK inhibitor already approved for treating some NF1-related tumors, lowered GDNF levels in Schwann cells and reduced pain-like responses in the mice. The study builds on earlier work showing that Schwann cells contribute to pain signaling in NF1 and further supports the idea that non-tumor nerve changes may play a central role in the disorder.

More study is needed to confirm that the same mechanism operates in people and that it can safely relieve NF1-related pain. If that work succeeds, co-authors say it may become possible to intervene earlier to give people with NF1 tumors less pain and improved levels of day-to-day function.

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