Let’s talk about paw-paw.

Rousting me out of my recent blog-post drought was some click-bait I saw about the growing popularity of a fruit called paw-paw.

The paw-paw fruit with its seeds

So-named because of its outward resemblance to papaya, paw-paw grows on trees both wild and cultivated, in the eastern US and Canada.  The flesh is sweet and creamy, like a banana, and can be consumed in many forms.  Maybe the only reason it’s not more popular is that the fruit is easily bruised during shipping.  It’s one of the faves of the locavore, farm-to-table movement in eastern North America.  So, what’s not to like?

Here’s what: Paw paw contains a mitochondrial toxin called “annonacin.”  It’s not only on the seeds, leaves and roots, where toxins exist in many plants with harmless fruit, but also in the fruit itself.  The toxin inhibits the action of “complex I,” a critical part of the process in the mitochondria that makes energy from sugars and oxygen.  It seems likely that the toxin serves the plant as a defense against insects, whose mitochondria, like ours, are susceptible to it.

Annonacin first reached the attention of scientists studying neurodegeneration after the 2002 publication of a description of a tauopathy endemic on the Caribbean island of Guadeloupe.  A third of the people with that disease met diagnostic criteria for PSP. The others had falling, frontal cognitive loss and disinhibited emotional responses, but not the eye movement palsy of PSP.  Compared with people on Guadeloupe with typical Parkinson’s disease or healthy controls, those with “Guadeloupean tauopathy,” as it came to be called, were far more likely to have consumed a tropical fruit called soursop. You guessed it: soursop turns out to have harbor annonacin, like paw-paw.

Prompted by that information, scientists in Germany injected annonacin intravenously into rats.    The result was a tauopathy that resembled PSP in the rats’ motor behavior and in the appearance of their brain cells under the microscope. The same group subsequently found that annonacin can cause tauopathy by a very different mechanism as well.

Shortly thereafter, I did a dietary risk factor survey among my patients with PSP, comparing them to controls with non-degenerative neurological diseases from our clinic.  So few had ever eaten paw-paw (or soursop) that the study didn’t have the statistical power to answer the question and I never published it.  (The more common foods included in the questionnaire gave no statistically significant results, either, in case you were wondering.)

Bottom line: There’s probably not enough annonacin in paw-paw to cause PSP or other tauopathies after only occasional consumption.  But over decades?  And what about people with a genetic predisposition to develop tauopathy?  Or people who just love paw-paw and eat them like candy? (There are some!) I think more research and some careful thinking by the FDA is needed before paw-paw becomes more widely marketed and consumed alongside apples, bananas and oranges.

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.