Tag Archives: pathogenesis

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.

Six horsemen of the Apocalypse

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I watched a scientific presentation today in which the speaker started off by summarizing the leading theories of PSP’s pathogenesis.  That means not the external influences such as the genes received from one’s parents or whatever toxins or other stresses might help cause PSP in susceptible people.  Rather, it means the abnormal processes set in motion and operating inside in the brain cells leading to their dysfunction and eventually, their death. 

Here’s a quick rundown for you:

  • Tau splicing.  The tau protein is encoded by the MAPT gene, which has 14 sections called exons encoding separate fragments of the final protein.  These protein fragments are then stitched together, but sometimes one or more of them is omitted by design.  In healthy people, the product of exon 10 is included in about half of the final tau molecules, but in the tau tangles of PSP, that fragment is nearly always included.  This makes the tau more likely to aggregate.
  • Tau post-translational modifications. Many or most proteins have very small molecules attached to them at specific points to regulate their function and direct their folding pattern.  The abnormal tau of PSP has phosphate and other molecules in inappropriate places.  This could help explain the abnormal folding, which in turn produces toxic aggregates.
  • Tau degradation. The normal “garbage disposal” systems of brain cells gets rid of proteins or organelles (the tiny structures in cells that perform specific functions) that are either overproduced, defective or just worn out.  There are two basic kinds of such systems, the ubiquitin-proteasome system and the autophagy-lysosomal system.  Neither works as well as it should in PSP.  This allows abnormal tau and other toxic molecules to accumulate.
  • Intracellular tau spread. In many neurodegenerative diseases, the abnormally folded tau can travel from one brain cell to another, causing normal copies of those molecules to misfold in a similar fashion.  This creates a kind of chain reaction spreading the damage widely. The misfolding pattern of the tau is specific to each of the tauopathies.
  • Mitochondrial dysfunction. The mitochondria are the organelles in the cells that harvest energy from sugars with the help of oxygen.  In PSP, they function abnormally, possibly because of their own genetic mutations, possibly because their biochemistry is particularly sensitive to certain toxins in our environment.  Mitochondrial dysfunction doesn’t just deprive the cell of energy – it also produces toxic compounds such as free radicals that damage other cell components.
  • Gene expression errors. The most recently discovered pathomechanism has to do with abnormal regulation of access of the cell’s protein-making machinery to the DNA “blueprint.” That process is normally regulated by proteins collectively called “chromatin,” which coat and intertwine with the DNA in the nucleus.   One way the abnormality might work is that abnormal chromatin permits inappropriate access to certain genes that stimulate the immune system, producing a harmful inflammatory reaction in the brain.

All of these pathogenetic mechanisms except the first are currently being addressed by drugs in advanced stages of the development pipeline.  I really don’t know which horse to put my money on.