The same brain protein behind mad cow disease may also help us remember
Every human nerve cell carries a protein called PrP, and nobody is quite sure what it is for. When it folds into the wrong shape, it drives fatal brain illnesses such as mad cow disease and Creutzfeldt-Jakob disease. In its normal shape, experiments hint it helps with memory, sleep and handling copper.
The protein is built from instructions in the PRNP gene on the short arm of chromosome 20. It starts as a chain of 253 amino acids, trimmed to 208 once signal sections at each end are removed. The mature molecule has a compact region of three helices and a small two-strand sheet, plus a flexible tail, and it is tethered to the outside of the cell membrane by a lipid anchor. That anchor turns out to matter: versions of the protein without it are not converted by the infectious form. PrP is so similar across mammals that findings in mice carry weight, and among primates the sequences match by 92.9 to 99.6 percent.
The dangerous form has exactly the same sequence but a different shape. Where the normal protein is largely helical, the misfolded one has no helices at all, stacking into tough fibres held together by sheets that resist enzymes that would normally break it down. The leading idea is that contact with the misfolded form forces normal copies to refold and clump. Strong support comes from mice lacking the gene, which cannot be infected. In sheep, particular gene variants resist scrapie, and Britain has tried to breed for them.
What the healthy protein does is still debated. Its repeated segments bind copper, zinc, manganese and nickel, and it may shuttle copper into cells or buffer it at synapses, where it is most concentrated. Mice without it keep normal short-term memory but struggle to consolidate long-term memories and to learn spatial layouts; restoring PrP in neurons brings spatial learning back. Human studies focused on position 129 in the protein link its variants to memory ability and the pace of cognitive decline.
Sleep is involved too. The inherited disease fatal familial insomnia traces to a change at codon 178, and PrP messenger RNA rises and falls with day and night. More than 20 mutations in the gene cause inherited prion diseases.
Source: Major prion protein
