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.