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  Technically unpublished, it didn’t appear in my daily electronic searches of the PSP literature via Pub Med.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.