Monthly Archives: July 2025

Testing our metal

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My post from two days ago was about a 2024 paper that had just won an award from the Alzheimer’s Association.  It found and confirmed some subtle genetic risk factors for PSP.  One of them has to do with the part of the immune system called the complement cascade because it complements the role of antibodies. 

The finding on the complement-related gene prompted me to update my theory of the cause and pathogenesis (the subsequent sequence of events in the brain) of PSP.  That includes exposure to metals, at least in some cases. 

In response to that, a commenter asked which specific metals I had in mind. I responded directly in the comments section, but I thought it would make a good post for today:

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We don’t know which specific metals might be involved in the cause of PSP, or how important they would be relative to other causes we don’t yet understand

  • The formal case-control surveys implicating metals asked about metals in general. Besides, that association was weak and lost statistical significance after other exposures were accounted for as confounders.
  • US Army veterans who developed PSP years later were more likely to have frequently fired weapons during their service than other Army veterans without PSP. So that incriminates lead, but gunfire undoubtedly aerosolizes other metals as well. My quick search reveals that gunfire can aerosolize aluminum, antimony, barium, cadmium, chromium, copper, iron, lead, manganese, nickel, tin, tungsten and zinc.
  • The PSP cluster in a couple of adjacent industrial towns in France suggests chromium, but that’s only the most important of the many metals contaminating that environment. Others with circumstantial associations are arsenic, copper and nickel, but others must exist as well.
  • The metals that caused PSP-susceptible cultured neurons to develop tauopathy in a 2020 lab study were chromium and nickel, but other metals weren’t tested because of insufficient lab capability at that time.

So that’s it, and it’s not much. It would be great if the existing genetic risk data could be analyzed for genes involved in metals detoxification. They might have fallen below the threshold of statistical significance for a genome-wide study, but a much more focused gene marker study might be able to show an association with the disease.

It could also be fruitful to analyze available autopsied brain tissue from the French cluster for metals content, comparing it to controls without PSP from the same contaminated area and elsewhere.

Also, let’s not forget that it might take certain combinations of metals, or of metals with other toxins, to increase one’s PSP risk. That could explain why there’s only one known geographical cluster of PSP — that area in France was multiply contaminated.

Nick Charles at the dinner party

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What’s really fun about blogging is that I can express scientific or medical opinions without having to get past experts like peer reviewers, journal editors or conference organizers.  (Hence most of the evil trash on the Internet.) 

But a frequent, insightful commenter called “mauraelizabeth3” asked this question after reading my last post about a new genetic finding in PSP incriminating to the myelin-producing cells, the oligodendrocytes, as a major possible starting point for PSP.

Is it known how these findings relate to (or perhaps result in) the hyperphosphorylated tau protein that aggregates in the brains of PSP patients?

I’ll respond to that excellent question with my own current theory of the etiology and pathogenesis of PSP.  It’s based on legit science, but of course, I don’t really know how much emphasis to place on each of the disparate current facts, or how many additional facts await discovery.

Dear me3: 

That’s really the question, isn’t it!  My own formulation at this point is that the loss of myelin from those multiple gene variants is a sideshow that impairs neurological function but isn’t actually part of the cause of PSP.  Instead . . .

  1. I’d propose that the first abnormal event is some inherited or de novo mutations or epigenetic alterations in the MAPT gene (which we know do exist in PSP) changes the structure or the post-translational modifications of tau in a way that stimulates its hyperphosphorylation as a reaction designed to facilitate its degradation.  Hyperphosphorylation tau might also be the result of some sort of toxin exposure, with metals currently the leading contender.
  2. Then, hyperphosphorylated tau falls off the microtubules and is free to do mischief all over the cell.  Maybe the first (or only) thing it does is to make the genomic DNA in the nucleus lose some of its protection against inappropriate transcription into RNA.  It’s been shown that such inappropriate transcription allows retrotransposons to be transcribed.  (Those are pieces of DNA implanted there by viruses millions of years ago.  They have reproduced themselves to other parts of the genome and now account for about 40% of our DNA.)  
  3. The RNA so produced is recognized by the immune system as viral.  An immune response ensues, which attacks and degrades a lot of RNA and innocent bystanders.  The resulting molecular garbage is a major challenge for the cell’s regular garbage disposal, the ubiquitin-proteasome system and the autophagy/lysosomal system. 
  4. Meanwhile, all that hyperphosphorylated tau is misfolding and then aggregating with itself.  This does take place under normal, healthy conditions to some extent, and the disposal systems can handle that.  But now, with the garbage from the inflammation and the unusual amount of aggregated tau to degrade, the garbage disposal is overwhelmed.  This allows all sorts of normal toxic garbage to accumulate, and that’s eventually fatal to the cell. 
  5. This whole process starts in the astrocytes or oligodendrocytes and spreads to the neurons courtesy of the microglia (the brain’s immune cells), synaptic connections and direct contact. 

Keep in mind that I’m a clinician with little laboratory experience beyond delivering fluid samples from my patients to my smarter colleagues with the pocket protectors.  But I try to keep up with the latest in all aspects of PSP, and there’s lab support for all of the assertions in my hypothesis.  It’s just that putting those facts together is tricky, like cracking a complicated criminal plot.  I hope that my hypothesis at least illustrates that we’re starting to get more of a handle on the pathogenesis of PSP.

Thanks for the complement

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The Alzheimer’s Association’s division devoted to frontotemporal dementia and related disorders has just announced its award for best publication of the year for 2004.  It’s entitled, “Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes.” The lead author is Dr. Kurt Farrell of the Icahn School of Medicine at Mt. Sinai in New York, and the senior author is Dr. Adam Naj of the David Geffen School of Medicine at UCLA.  Full disclosure: I played a very minor role in an early phase of the work and am 34th of the 48 co-authors.

The study sought to identify new genes conferring risk for PSP by comparing genetic markers between a group of 2,779 people with PSP (a large majority autopsy-confirmed) and 5,584 people with no neurodegenerative conditions.  This is the largest such study in PSP to date, the first having been published in 2011. The study’s large size gives it greater power to distinguish a genuine PSP-related genetic variant from a statistical fluke. 

This technique can identify not a specific gene, but a small region of a chromosome, typically with 50 to 200 genes.  But the researchers then nominated a couple of the most likely genes in that region and tested brain tissue for excessive amounts or abnormal forms of the protein encoded by the candidate genes.

Besides confirming PSP’s previously-identified genetic risk factors, Farrell and colleagues identified a new risk gene called C4A, located on chromosome 6. The protein it encodes is part of the cell’s “innate immune system.” The C stands for “complement,” a complicated group of proteins that assist the antibodies.  Once an antibody latches onto an unwanted invader like a bacterium or virus, proteins from the complement system attach to the other end of the antibody, initiating a series of interactions that eventually produces an “attack complex” that pokes a major hole in the invader.

The other important finding from the same study was a strong tendency for all the genes known to increase PSP risk to affect the oligodendrocytes.  Those are the brain cells that form the myelin sheath insulating the axons of most of the brain’s neurons, greatly facilitating electrical conduction.  We’ve known for decades that loss of myelin is an early feature in PSP, and that some PSP risk genes encode proteins related to oligodendrocytes.  But the new paper provides important confirmation in a larger patient group, using techniques not previously available.

So, bottom line: Although the genetic basis of PSP is not usually enough to make the disease occur in more than one member of a family, it could still be one important factor, along with things like a poorly-understood toxin exposure.  Furthermore, the new evidence that the oligodendrocytes might be the first cells to get sick in PSP points researchers in that direction in their search for new, easily addressable drug targets.  Plus, the discovery that an important part of the immune system could be what’s ailing the oligodendrocytes means that the array of potential drug targets is now much better focused. Shotgun approaches to taming components of the complement system have been under way for about a decade now, and the new finding of Farrell et al could focus those efforts nicely.