A new drug target from an epidemiologic observation

I think what jolted me out of my multi-month posting torpor is next week’s annual meeting of the Movement Disorders Society. I’ve been preparing a lecture on the treatment of PSP, CBD and MSA, and that got my juices flowing.
Speaking of treatment, an interesting paper that appeared in Plos One during my writer’s block came out of Günter Höglinger’s lab in Munich. Julius Bruch was first author. It builds on the observation that people with Guadeloupean tauopathy are far more likely than local controls to have consumed the fruits sweetsop and soursop, which contain annonacin, a mitochondrial Complex I inhibitor. Subsequent work with annonacin has suggested that it can cause a tauopathy in rats.
The new paper found that annonacin upregulates the production of 4R tau, the predominant form in PSP and some other tauopathies, by favoring the inclusion of the exon 10 peptide product into the finished tau molecule. Further experiments described in the same paper showed that annonacin upregulates the splicing factor SRSF2, which is one of a handful of factors known to regulate splicing of exon 10. So they used silencing RNA to knock down SRSF2. The result was a dramatic reduction in 4R tau.

They then took the next step and analyzed human PSP brain tissue for SRSF2, finding it markedly elevated compared to controls with no neurological disease.

To examine the possibility that the elevation of 4R tau and SRSF2 by annonacin was the result of mitochondrial Complex I inhibition rather than of nonspecific cellular stress or nutrient deprivation, they treated neuronal cultures with MPP+, a well-studied Complex I inhibitor, but not with 6-hydroxydopamine, a toxin that works independent of Complex I, or with nonspecific nutritional deprivation.

So it looks like a drug that inhibits SRSF2 could correct the abnormal 4R/3R ratio in PSP and potentially prevent cell loss. But a lot of work remains to determine how important this particular pathway is in causing the cell loss. The highly variable 4R/3R concentration across different brain areas in PSP and the existence of tauopathies with normal or low 4R/3R ratios show that the story isn’t so simple. But with the recent explosion of interest from drug companies in PSP as a route to Alzheimer’s disease, any new approach could attract interest, and this one deserves a place on the list.  I don’t know if any existing or approved drugs inhibit SRSF2, but that could be a good job for a lab that’s tooled up for high-throughput screening.

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One thought on “A new drug target from an epidemiologic observation

  1. I reacted to the word “Epidemiologic” of your title. As a close relative to a PSP patient, I read several “PSP Boards” where PSP patients and relatives can express their emotions and testify of their experiences. Because there are no real cures at the moment, people are tempted to try whatever they can find. Easy to understand when you go through the frustration of a PSP Patient ou relative. Time to time you go through a very positive experience and you wonder: does it make sense, is that possible, is it being studied somewhere?
    I feel that these boards are not suffisiently exploited by professionals. It could used as a source of inspiration and trigger some innovative ideas.
    As an exemple, a poster recently mentioned spectacular improvement of his symptoms after having taken adiatery supplement containing Methylcobalamine (the methyl form of vitamin B12) and Benfotiamine ( Vitamin B1).I made a quick investigation and found out that this methyl form of vitamin B12 is the only one capable of crossing the BBB (Blood Brain Barrier). This guy has absolutely no idea why it would work, neither do I and presumably neither “specialist” do as well.
    But if we are prepared to take this kind of observations by non-specialists with humility, we could may be come out with a new research directions. I am myself a retired PhD having managed big research organizations (hundreds of top PhDs) and learned that many innovations come from astute observations made by smart people not necessarily knowledgeable in the field.
    What could we do to better exploit this mine of data (rather testimonies than data to be precise) and have you ever see any organization looking at the effect of Vitamins capable of crossing the BBB on neurodegenerative illnesses?

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