If you know anything about PSP at its molecular level, you know that the tau protein in the neurofibrillary tangles is almost entirely of the “4-repeat” or 4R variety. The other kind is “3-repeat” or 3R. Normal adult human brain has equal amounts of 3R and 4R. So do the tangles of Alzheimer’s disease. But the tangles of Pick’s disease are 3R.
The thing that’s repeating is the section of the protein that binds it to microtubules, the brain cells’ internal skeleton and monorail system for transporting chemicals along axons. The gene encoding tau, called the “microtubule-associated protein tau” (MAPT) gene, has four sections, called exons, each encoding one microtubule-binding repeat. MAPT has 16 exons and the four in question are exons 9, 10, 11 and 12. 4R tau includes the repeat encoded by exon 10 and 3R tau doesn’t.
There’s pretty good evidence that in PSP, the extreme imbalance of 3R and 4R tau is a major factor in making the tau toxic to brain cells. But why can’t the brain cells in someone with PSP make enough 3R tau? In other words, what prevents the brain cells in PSP from excluding the repeat from exon 10 half of the time, as normal brain cells do?
In the latest issue of the journal RNA Biology, a group mostly from McMaster University in Hamilton, Ontario, Canada report at least part of the answer. They have found that the protein called “heterogeneous nuclear ribonuclear protein C” (hnRNPC) prevents the normal process from happening by binding to messenger RNA. hsRNPC has been known for years in relation to certain types of cancer, but its role in the brain or in neurodegenerative disease was not previously well studied. To accomplish this work, the team developed a new technique called “RNA antisense purification by mass spectroscopy” (RAP-MS). They also found, critically, that in PSP brain, the level of hnRNPC is abnormally elevated, an important confirmatory observation. (Why is it elevated? I can’t wait for the next installment in this story!)
The authors point out that hnRNPC can now be considered a target for drugs to slow or halt the progression of PSP. Pharmaceutical companies, take note.
The senior author of the study and lab head at McMaster was Yu Lu, PhD, a specialist in proteomics. His grad student Sansi Xing was first author. The team included others from McMaster, the University of Iowa in Iowa City and Mount Sinai in New York.