Common thread, silver bullet, naïve hope?

There’s a great place on the Internet called bioRxiv (“bio archive”), where researchers can post their papers without benefit of peer review.  Users know that they’re reading the latest, but the greatest?  Maybe only its authors and their mothers think so.  But when a paper is from a group of researchers with stellar reputations, it’s probably the real deal.

Such is the case for “Age-dependent formation of TMEM106B amyloid filaments in human brain,” posted on the bioRxiv website in November 2021.  Most of the 29 authors, including the leading ones, are from University of Cambridge or elsewhere in the UK, but many are from various institutions in Japan, with a few from the Netherlands, Canada, Austria and the US.

The paper found that the brains of healthy elderly persons have abnormal aggregates of a misfolded form of the protein TMEM106B. This stuff is known to be a component of healthy lysosomes and endosomes, components of the cell’s garbage disposal mechanism.  Variants in the gene encoding TMEM106B elevate one’s risk of developing the TDP-42 type of frontotemporal dementia.  The term “amyloid” in the paper’s title doesn’t refer to the beta-amyloid of Alzheimer’s disease but to its more generic sense of any protein aggregated into insoluble clumps.  Tau in PSP, for example, is an amyloid. 

Not only did the bioRxiv paper discover amyloids of TMEM106B in normal aging, it found them even more abundantly in a raft of neurodegenerative diseases: Alzheimer’s, CBD, multiple types of FTD, Parkinson’s, dementia with Lewy bodies, multiple system atrophy and multiple sclerosis.  Notice that PSP isn’t on the list.  That’s because none of their 22 brain samples were from people with PSP. 

So last week, into the breach rides a paper that has actually been peer-reviewed and published — in Cell, no less.  (A very prestigious, selective journal.)  Those authors, from Columbia University, Mayo Clinic Jacksonville and a number of other places in the US, Canada and Belgium, found the same TMEM106B aggregates in both of the brains they examined from people with PSP.  They knew of the bioRxiv paper and cited it.  (That’s how I found the bioRxiv paper.  Technically unpublished, it didn’t appear in my daily electronic searches of the PSP literature via Pub Med.   I doggedly tracked it down on the bioRxiv website only after I saw it cited in the new Cell paper.  See what I do for you, my dear readers?)

An interesting finding is that unlike tau, TMEM106B misfolds the same way in all the diseases analyzed so far.  This may have huge potential implications: if (and this is a big “if”) the misfolded TMEM106B plays an important role in the formation of the misfolding and toxicity of tau and the other disease-specific proteins, and if (another big “if”) this misfolding is the rate-limiting step in the loss of brain cells in the neurodegenerative disorders, THEN preventing TMEM106B from forming or from misfolding, or targeting it with antibodies or drugs could be the silver bullet that prevents all of these diseases, PSP included.

That could be a naïve hope, but I’ll ask some hard-bitten old lab codgers bearing the scars of past failed grand theories what they think.

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.

A few tidbits from Tau 2022

Here are some very quick research updates from the Tau 2022 meeting of February 22-23.  Most of this is unpublished, so I can’t get into much detail.

Oral tau expression modulators. Drugs that modulate the production of the tau protein are currently in clinical trials but are administered by injection, typically directly into the spinal fluid.  Not very practical.  But now, orally administered drugs that do much the same thing are being developed and have drug company interest.

New drug trial?.  A drug called lonafarnib, which inhibits an enzyme called farnesyl transferase, is FDA-approved for one form of pathologically early ageing in children.  It has also been known for a couple of years to slow progression in a mouse model of tauopathy by enhancing the action of lysosomes, which break down excessive tau.  Now, it’s being studied in healthy human volunteers and a trial in people with tauopathies may not be far off.

A tau inflection point.  In Alzheimer’s disease, positron emission tomography (PET) scanning for tau has shown that in the first few years, before the symptoms become very troublesome, the tau burden in the brain is increasing slowly.  But then, at about the time the symptoms bring the person to medical attention, the tau burden dramatically increases and continues to do so thereafter.  That tipping point has been informally and perhaps disrespectfully called a “ca-tau-strophe” beyond which the process may not be amenable to slowing by any treatment.  We don’t know if the same thing happens in PSP, but it seems likely.  This is further justification for improving the sensitivity of diagnostic methods and for better educating health professionals about PSP.

New gene “knock-in” models. Frontotemporal dementia is strongly hereditary in about a third of cases.  Of these, 4% have a PSP-like picture, 5% are PD-like and 2% are CBD-like.  The average onset age of hereditary FTD is only 50, compared with about 65 for true PSP.  (True PSP occurring in a familial pattern is much rarer and no mutation for that has been identified.)  So far, 71 different mutations in the tau gene have been found as causes of hereditary FTD.  A few of those have individually been inserted into mice to create commonly used models for PSP and Alzheimer’s research.  Those mouse models have taught us a lot, but drugs that slowed progression of the tauopathy in such mice have uniformly failed in human clinical trials of AD or PSP.  However, many mutations in other genes have been found to confer a small degree of risk for AD or PSP.  Presumably, someone with AD or PSP must harbor at least two such mutations.  Now, researchers have created mice with multiple such mutated genes, hoping that they will provide a more faithful mimic of human tauopathy for use in screening drugs before embarking on human treatment trials. 

PSP blood test challenges.  Tau protein with abnormal attachment of phosphate groups in certain positions is increased in the blood of people with Alzheimer’s disease.  This can serve as a diagnostic tool.  But the same isn’t true for PSP, unfortunately.  This may be because there’s less abnormal tau in the brain in PSP.  But in PSP, unlike in AD, the glial cells of the brain have more abnormal tau than the neurons, and a new type of blood test can differentiate between tau from the two brain cell types.  This requires measuring tau in tiny, membrane-bound droplets in the blood called “exosomes.”  Work to assess the diagnostic potential of exosomes in PSP is ongoing.

PSP as an immune disorder. The tauopathies have been found to involve changes in immune function and the part of the immune system involved is different in the various disorders.  In PSP and CBD, for example, the “natural killer” (NK) lymphocytes are more involved, while in Alzheimer’s, it’s more about the microglia.  PSP has been found to have a set of gene variants related to glial function and another related to NK lymphocytes that tend to be suppressed to the similar degrees, meaning that the disease may result, in part, from simultaneous insufficiency of these two functions.

Another set of dispatches from the Tau 2022 meeting soon — I promise.