Post-post modifications

Since yesterday’s post about the discovery of the detailed pattern of tau misfolding in the various tauopathies went live, some discussions with colleagues and laypersons have prompted me to bang out the following Q/A:

Q: Does the newly discovered, major difference in tau folding between PSP and CBD mean that CurePSP and researchers interested in PSP will devote fewer resources to CBD going forward?

A: Absolutely not.  The two diseases still have a lot more commonalities than differences and each will continue to benefit from research and patient care insights into the other.

Q: Does this new information mean that PSP has less value as a test bed for treatments aimed at Alzheimer’s disease?

A:  Only very slightly.  All of the tau-based treatments in the research pipeline are aimed at tau in general, not any specific folding pattern.  Over time, it may emerge that the parts of the tau molecule that are more “buried” within the folding structure are less able to interact with antibodies or drugs.  If that inaccessible section is different in PSP compared with in Alzheimer’s, then a drug company or researcher interested in AD may decide to direct their efforts accordingly.  But most of the tau molecule will probably prove to be equally accessible, for practical purposes, in all of the folding conformations, in which case, PSP will remain as valid as ever as a test bed.

Q: How definite is the new discovery?

A: Like any scientific discovery, it needs to be confirmed by different researchers in different labs using slightly different techniques. 

Q: Will the new discovery accelerate finding a prevention or cure*?

A: Possibly, and it’s hard to say by how much.  An effective prevention or cure may not care about the specific tau folding pattern.  For example, a very promising type of prevention now entering clinical trials is anti-sense oligonucleotides (ASO’s), which are small strands of RNA that prevent the genetic code for tau from being translated into tau protein.  The misfolding occurs at a later stage, so an ASO directed at tau should help reduce tau production in any tauopathy.  (Whether the amount of tau production is the key to the disease is another question.)

*Technically, a “cure” requires not only halting of the disease progression but also repair of the existing damage.  Those are two different things, and the latter is more difficult to achieve for a complex structure like the brain.  If we can find a way to diagnose PSP in its earliest stages, before there’s enough damage to cause symptoms, then all we need is a way to prevent further damage.

Q: What determines the tau folding pattern in the first place?

A: Any of several things that we know of, and there are undoubtedly more that we don’t yet know of.  The leading candidate is the attachment of small molecules to the tau protein that affect its ability to bend and to stick to itself.  The most common such molecule by far is phosphate (one phosphorus atom and three oxygen atoms) but others are various sugars, lipids, acetyl groups, sulfyl groups, methyl groups and dozens of others (Wikipedia has a nice list). These are called “post-translational modifications” (PTMs) and they’re normal, but like any normal biological process, they can go awry.

Other things causing protein misfolding in some disorders are environmental toxins and genetic abnormalities.  We don’t yet know the relevance of these to PSP or CBD, but there are some indications that it’s not zero.

We don’t know why certain diseases have abnormalities of PTMs.  We don’t even know, in most cases, if the abnormal PTMs are a cause of the tissue damage or a collateral effect of the same toxic process that causes that damage.  The new information about tau folding patterns will certainly intensify the already intense search for those answers.

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