Normal Prion Protein Maintains Myelin Integrity in Nervous System

Researchers studying chronic diseases of the brain have determined the function and mode of operation of the cellular prion protein PrPC, which in its cytotoxic form underlies prion diseases such as spongiform encephalopathy (mad cow disease) and its human counterpart, variant Creutzfeldt-Jakob disease.

Previous studies conducted by investigators at the University of Zurich (Switzerland) demonstrated that mice lacking PrPC had disruptions in the myeloid sheath, the insulating material derived from Schwann cells that surrounds nervous system axons, but the reasons for the disruptions were unclear.

In the current study, the University of Zurich researchers collaborated with investigators from the Washington University School of Medicine (St. Louis, MO, USA) to determine the role and mode of action of normal PrPC.

The investigators reported in the August 8, 2016, online edition of the journal Nature that the cAMP concentration in sciatic nerves from PrPC-deficient mice was reduced, suggesting that PrPC acted via a G protein-coupled receptor (GPCR).

Working with mouse and zebrafish models, the investigators showed that PrPC attached to a GPCR on Schwann cells called Gpr126. The amino-terminal flexible tail (residues 23–120) of PrPC triggered a concentration-dependent increase in cAMP in primary Schwann cells, in the Schwann cell line SW10, and in HEK293T cells that over expressed Gpr126. By contrast, naive HEK293T cells and HEK293T cells expressing different GPCRs did not react to the flexible tail, and removal of Gpr126 from SW10 cells abolished the flexible tail-induced cAMP response.

“Previous studies have suggested a role for prion proteins in maintaining neurons, but until now, no one knew how the properly folded versions of the proteins function,” said contributing author Dr. Kelly R. Monk, associate professor of developmental biology at Washington University School of Medicine. “It is surprising to see that the protein has a role in maintaining the structure of nerve cells, considering that a misfolded version of PrPC is known to cause fatal brain diseases.”

“We have identified a definitive function for the normal prion protein and clarified how it works on a molecular level,” said senior author Dr. Adriano Aguzzi, professor of neuropathology at the University of Zurich. “Our study answers a question that has been intensely researched since the prion gene’s discovery in 1985.”

Related Links:
University of Zurich
Washington University School of Medicine