A family matter

Want to know what’s hot in lab research on PSP?  Or, more accurately, want to know what will be hot in a year or two?  This week, CurePSP will announce its four newest research grant awardees.  Most of the 20 competing applications, a very large crop for CurePSP, were of excellent quality and in a less competitive cycle many of them would have been funded.   A fifth and possibly a sixth application may be funded next month after CurePSP’s leaders have had a chance to discuss the use of a new, unexpected, seven-figure donation.

Since I’m driving this bus, I’ll start with the funded grant I consider the most intriguing, though it’s the smallest of the four.  For two decades, researchers at the University of Southern California have been following a Mexican-American family with PSP in 14 members over three generations.  Two of the 14 have had autopsies confirming the diagnosis.  The inheritance pattern is most likely autosomal dominance (look it up).  There are six living, affected members and another 19 who are at 50% risk because they have an affected parent or sibling.  One of the affected members has had sequencing of the gene that encodes tau (called the MAPT gene).  That revealed no mutations.  Now, John M. Ringman, PhD and his USC colleagues plan to sequence the entire genome of four affected and one unaffected family members.

It’s entirely possible that the result will be a mutation in one of the half dozen or so genes besides MAPT that have already been identified by other methods as conferring a slight risk of developing PSP.  That wouldn’t be so exciting, though it would show that one mutation in that gene suffices to cause the disease while other mutation(s) in the same gene only raise PSP risk slightly.  That would shed light on just how that gene works with respect to PSP.

A more exciting result would be if the culprit gene in this family turns out to be one that has not been previously associated with PSP.  Even though this particular mutation would clearly not be the cause of “regular” PSP, perhaps the protein that this gene encodes will prove to be part of a molecular pathway critical to the pathogenesis of PSP but not yet investigated carefully.  That could point to scads of new treatment targets for drug developers and maybe even a diagnostic test.  Very cool.

I led a project like this on Parkinson’s disease back in the 1980s and 1990s, though we didn’t have whole-genome sequencing then.  I won’t get into the details, but you can read about the big family I found and worked with here, my subsequent clinical analysis of the family here, the report of the culprit gene here, the discovery of its significance to PD in general here, the development of a diagnostic test based on the gene’s product here, the efforts to prevent PD in lab models by reducing the gene’s product here and an initial safety report on a Phase 1 human trial here.  Maybe that’s why I find Dr. Ringman’s little project so intriguing.

More on the other new grantees in the next post.

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