on the tau molecules could simply be how the brain minimizes the effects of tau protein that is misbehaving for some other reason.
Regardless of its origin, the excessive phosphate on the tau protein molecules causes the tau to misfold. Ordinarily, tau protein that’ s not attached to microtubules floats around without a fixed shape in the cell’ s fluid, like a strand of overcooked spaghetti in boiling water. But when it misfolds, it assumes a more rigid structure, like a strand of dried-out spaghetti. Like spaghetti, it’ s sticky and it forms clumps with other misfolded tau molecules.
In the past few years, evidence has been discovered that a single strand of misfolded tau can cause normal, freely floating copies of tau protein to misfold in the same way. This is called a templating process. The newly misfolded copies then cause other copies to misfold, and so on, in a chain reaction. Then the misfolded tau molecules start to clump. The clumps are toxic to the cell, which eventually dies. Even before the cell dies, it releases misfolded, clumped tau protein into the fluid surrounding the cells. That tau is then taken up by neighboring healthy cells that undergo the same damaging chain reaction of tau misfolding, templating, and clumping. In this way, the process of brain cell malfunction and death spreads slowly through the brain. A similar process is thought to occur in most of the neurodegenerative diseases but with different kinds of proteins in different diseases. This insight raises the tantalizing possibility that a drug that prevents that templating process could prevent all neurodegenerative diseases.
Since the 1980s, it’ s been known that one type of protein in the cell, called prion protein( pronounced PREE-on), does in fact misfold, template itself, and form toxic clumps to cause certain neurodegenerative diseases, such as mad cow disease and Creutzfeldt-Jakob disease. Those diseases progress very rapidly and can be transmitted from one individual to another via exposure to diseased tissue. But misfolded prion protein behave very differently from misfolded tau protein, and PSP, Parkinson’ s, Alzheimer’ s, and the other neurodegenerative diseases progress far more slowly and are not transmittable between people. They should not be lumped with the true prion diseases.
17
Is PSP genetic?
PSP only very rarely runs in families. Fewer than one in 20 people with PSP knows of even one other family member with PSP. Detailed neurological exams of relatives of patients with PSP show no more definite abnormalities than exams of relatives of healthy people. However, two different variants in the gene on chromosome 17 that encodes the tau protein are more common in PSP than in the rest of the population. One of the variants is called the H1 haplotype. About 95 % of people with PSP have this variant on both of their copies of chromosome 17, while this is true for only about 60 – 77 % of the rest of us. So clearly, the H1 haplotype is( nearly) necessary but far from sufficient to cause the disease.
We’ re still not quite sure how the H1 haplotype increases PSP risk. One possibility is that it simply increases the amount of tau produced, which causes that protein to stick together, even if it’ s not misfolded. Another possibility, discovered only recently, is that it causes too many methyl groups to stick to the tau gene, which alters its function. A methyl group is simply a carbon atom with three hydrogens that can attach to large molecules, including DNA. Methylation is a normal way for the cell to regulate the function of DNA, thereby affecting the function of genes without actually changing the content of the genetic code like ordinary mutations do. This is exciting because certain molecules have the potential to be developed into drugs that could alter DNA methylation.