Proteomics hits paydirt

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. 

A clue from proteomics

The annual conference of the International Parkinson and Movement Disorders Society (“MDS”) is in progress this week on line.  The location of this meeting normally migrates from city to city world-wide and this year was supposed to be Philadelphia.  Nice city to visit – great history, great art, great restaurants (both fancy and ethnic).  Oh, well.  One of our many sacrifices to the pandemic and all things considered, not a serious one.

Of the 1,000 posters reporting new research, 17 were on PSP.  One that sounds very interesting is from Hiroshi Takigawa and colleagues at Tottori University in Yonago, Japan.  They did a proteomic survey of cerebrospinal fluid (CSF) from people with PSP, Parkinson’s, corticobasal syndrome and some healthy, age-matched volunteers.  Proteomics is a generic term for big-data studies of all the proteins in a biological samples, just as genomics is the study of all the genes.  In this case, they compared the collection of thousands of CSF proteins among the four groups listed and found that the only one that’s higher, on average, in PSP relative to the other three to a statistically significant degree is something called chromogranin B.  They also found that a small fragment of the 657-amino acid chromogranin B protein was the only protein (or fragment thereof) that was less abundant in CSF in PSP, on average, than in the other conditions. The fragment, which is only 31 amino acids long, is called bCHGB-6255.

For neither of these findings was the magnitude or consistency of the difference enough for use as a diagnostic test at the individual level.  (Statistical digression: For the biostatisticians among you, the area under the ROC for bCHGB-6255 was only 0.67.  For the rest of you, the receiver operating characteristic is a graph comparing the likelihood of true positives with that of false positives for the full range of possible definitions of an abnormal level.  The area under the ROC, if the each axis of the graph goes up to 1.00, has a theoretical maximum of 1.00, in which case there’s no risk of false positives in exchange for full identification of the true positives.  A result of 0.80 is barely acceptable for a test to be useful at the individual level and 0.90 is preferred.)

The value of the finding is the demonstration that chromogranin B might have something to do with the degenerative process underlying PSP but none of the related diseases.  Furthermore, the inverse relationship of the full chromogranin B molecule and its bCHGB-6255 fragment suggests that there’s something about the fragmentation process that may be uniquely important to PSP.  Maybe an enzyme that cleaves chromogranin B is deficient, damaged or suppressed in PSP.  Only further research will work that out.

What does chromogranin B normally do?  We don’t know.  It’s present in a wide variety of brain cells that use norepinephrine as their neurotransmitter and also in many cells in other organs.  It’s somehow associated with the secretion of norepinephrine and its blood levels are known to be elevated by certain tumors.  Tests for it are available from commercial medical labs.  But as I emphasized above, the test would be diagnostically useless at the individual level.

Most of the presentations at important meetings like the MDS are research that has not yet passed peer review, or at least not yet published.  So you have to take it with a grain of salt.  Of course, the same thing can be said for any research that has not been confirmed by other labs using other methods.  And even then . . . I’ll tell you about other interesting MDS posters in the next few days.