Pushing the envelope a little more

Three more clinically relevant, PSP-related reports from last month’s Tau 2022 symposium:

Barring entry to tau.  The way tau enters healthy cells in its spread through the brain has recently been found to be “receptor-mediated endocytosis.”  The same mechanism is used by many viruses, including influenza A,  Zika . . . and coronavirus.  Work is ongoing to identify genes encoding protein components of that process.  Then, inhibiting the production of such proteins could slow the spread of tau (not to mention those other diseases).  One of the proteins found to be involved in receptor-mediated endocytosis is LRRK2, which is mutated in a common, hereditary form of Parkinson’s disease.  The uptake of tau, at least by cells growing in a lab, is slowed by drugs that inhibit the most common PD-associated LRRK2 mutant, called G2019S (because a glycine at amino acid position 2019 is replaced by serine).  So this raises the possibility that such drugs, presently in trials for PD, could slow progression of tauopathies such as PSP.

PSP as a seizure disorder?  Some new evidence suggests that tau participates in the causation of PSP not by invading and destroying brain cells directly, but by getting a few brain cells too excitable.  This, in turn, could attract attention from the immune system, which over-reacts and causes slight damage to those and other brain cells, which causes more hyper-excitability, and so on in a vicious cycle.  This implies that a way to slow the progression of PSP could be anti-seizure drugs, which calm down hyper-excitability in brain cells.

Iron could be key. It turns out that in brain tissue from people with PSP, abnormal deposition of iron occurs in the same cells as the disease process.  It’s most pronounced in astrocytes, the type of cell in which PSP appears, based on several decades’ evidence, appears to start.  The researchers identified genes that are disproportionately “expressed” (i.e., actively coding their proteins) in the iron-laden cells.  This offers multiple new targets for drugs to act upon.

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